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MLLT10 binds CALM1. 349 / 349
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"Similarly, knockdown of TGM2 mirrored the effects of CTCF KO, impairing the proliferative capacity of CALM‐AF10 AML cells and promoting macrophage‐like differentiation."
40875517
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"However, TGM2 overexpression could not rescue the CTCF knockout phenotype (Figure  xref ), suggesting that TGM2 functions as only one component of CTCF's broader regulatory network governing CALM‐AF10 AML differentiation."
40875517
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"These findings strongly support the existence of a CTCF–TGM2 regulatory axis critical for maintaining the undifferentiated state of CALM‐AF10 AML cells."
40875517
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"GK921 [ xref , xref , xref , xref , xref ] (Selleck Biotech, Kanagawa, Japan), a TGM2 inhibitor, was investigated in CALM‐AF10 AML cells."
40875517
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"Within this subgroup of immature T-ALL, CALM-AF10 fusions are mostly seen in the AYA population with a median age of 25 years old, and are associated with an early resistance to treatment and a poor o[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
29050690
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"Oncogenic transcription factors can be divided into several groups: TAL1/2 , LMO1 /2, TLX1 /3, LYL , HOXA- translocations, MEF2C , NKX1/2 , CALM::AF10 , and KMT2A -rearrangements ( KMT2A -r)."
35011701
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"May Grunwald Giemsa staining and FACS analysis confirmed that GK921 induced differentiation of CALM‐AF10 AML cells into macrophage‐like cells, as evidenced by increased expression of F4/80 (Figure  xref )."
40875517
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"MN1 (Meningioma-1) is frequently over-expressed in AML patients and is associated with a poor prognosis. xref – xref However, in patients with inv(16), highest MN1 expression has been reported with favorable prognosis to current therapeutics. xref MN1 functions as a transcriptional regulator that co-operates with the nuclear receptors for retinoic acid (RAR) and vitamin D, by acting as co-activator or co-repressor, depending on the interacting partners. xref – xref In addition, MN1 is frequently over-expressed and occasionally fused to TEL as part of the rare MN1-TEL translocation. xref Mn1 is known to be co-operating partner of several oncogenic fusion genes (NUP98–HOXD13, xref CALM–AF10, xref MLL–AF9 xref and MLL–ENL) xref and mutated RUNX1, xref and as a common target of insertional mutagenesis in a hematopoietic stem cell (HSC) gene therapy trial, xref thereby promoting leukemogenesis."
31413090
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"These results indicate that GK921 effectively targets the undifferentiated state and proliferation of CALM‐AF10 AML cells."
40875517
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"Furthermore, ChIP‐qPCR analysis revealed that CALM‐AF10 binds to the HOXA locus but not to the TGM2 locus, suggesting that TGM2 is unlikely to be a direct transcriptional target of CALM‐AF10 (Figure  xref )."
40875517
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"This highlights the complexity of gene regulation in AML pathogenesis and suggests the need for further investigation into the indirect mechanisms by which CALM‐AF10 may influence TGM2 expression."
40875517
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"The identification of TGM2's significant role in CALM‐AF10 AML is pivotal for advancing our understanding of this disease."
40875517
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"The loss of CTCF suppressed leukemogenesis and disrupted the maintenance of CALM‐AF10 AML cells, driving differentiation into macrophage‐like cells."
40875517
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"AF10 PZP prevents the transforming activity of CALM-AF10 in vitro and in vivo."
34226546
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"Wild type CALM (or PICALM) is involved in clathrin-mediated endocytosis, and an almost entire CALM protein, including its ENTH domain and the clathrin-binding domain, are present in the CALM-AF10 chimera, being fused to AF10 in which the first PHD finger (AF10 PHD1 ) is deleted."
34226546
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"Much like other AF10 translocations, the CALM-AF10 translocation correlates with the upregulation of the proto-oncogenic HOXA and MEIS1 genes."
34226546
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"CALM-AF10 expressing cells show a local increase in H3K79 methylation on these genes but a global reduction in H3K79 methylation throughout the genome xref ."
34226546
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"In this study, we describe the biological function of the PZP domain of AF10 and its critical role in inhibiting the leukemogenic activity of the CALM-AF10 translocation."
34226546
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"Our results demonstrate that CALM PZP AF10 MF decreases Hoxa gene expression in CALM-AF10 MF leukemia cells and that incorporation of AF10 PZP in the leukemogenic fusion blocks the transforming activity in vitro and in vivo and abolishes CALM-AF10-driven leukemogenesis in vivo."
34226546
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"Altogether, our data suggest the molecular mechanism underlying the leukemogenic activity of the CALM-AF10 fusion (Fig.  xref )."
34226546
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"It has been shown that the nuclear export receptor CRM1 recruits CALM-AF10 to Hoxa loci via binding to the nuclear export signal of CALM xref ."
34226546
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"HOXA genes in particular are critical effectors of leukemogenesis and their expression is upregulated by various oncoproteins such as MLL fusion proteins, mutated NPM1 and CALM-AF10 [ xref , xref ]."
32343715
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"We have previously shown that the ability of CALM-AF10 to activate Hoxa genes is mediated by Crm1 [ xref ]."
32343715
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"CALM-AF10 interacts with Crm1 via a Nuclear Export Signal (NES) contained in the CALM moiety, and mutation of the NES or pharmacological inhibition of the Crm1/NES interaction abolishes the ability of CALM-AF10 to bind to and activate the transcription of Hoxa genes."
32343715
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"We found that Crm1 occupies Hoxa chromatin and proposed that it can tether CALM-AF10 to the loci of its effector genes."
32343715
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"Such early lineage infidelity may have clinical significance, since it has been shown that early B cell precursors can give rise to myeloid leukemia in CALM-AF10 (Picalm–Mllt10) transformed marrow cel[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
19944675
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"More common are cases of AML with both thymic or mediastinal involvement and BM infiltration xref , most notably patients with PICALM-MLLT10 ( CALM-AF10 ) fusions."
31748606
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"Besides the frequent fusions involving MLL1 in leukemia, two other recurrent translocations were demonstrated to cause malignant transformation by disrupting the normal function of DOT1L, namely the C[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
25592767
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"The 16 leukemia cell lines were derived from patients with high-risk disease including infants with KMT2A -r leukemia, one of the poorest outcome pediatric leukemias, T-ALL, mixed phenotype acute leukemia (MPAL), and CALM-AF10 translocated AML (Supplementary Table  xref )."
38349407
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"Additional testing revealed the CALM-AF10 fusion gene, a karyotype of del(5)(q31), t(10;11)(p13;q23), and mutations in NRAS, NOTCH1, WT1, KIT, MYB, and TET1 genes."
41185639
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"The CALM-AF10 fusion transforms immature HPCs in mice xref and causes T-ALL, B-ALL, and AML in humans xref ."
37031220
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"The minimum structural requirements of CALM-AF10 are the nuclear export signal (NES) of CALM and the OM-LZ domain of AF10 (see NES-AF10´ in Fig.  xref ) xref , xref , xref ."
37031220
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"CALM-AF10 expression was associated with altered Tfn uptake efficiency in 293T cells; however, endocytosis and proliferation were unaffected in a leukemia cell line [ xref ]."
25090048
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"Furthermore, compared to vehicle-treated AML cells, PTC-209 treatment also significantly reduced the clonogenic capacity of CALM-AF10 cells in CFU-assays in a concentration-dependent manner ( xref and xref )."
31022428
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"These results demonstrate that small-molecule BMI1 inhibitor significantly inhibits the proliferative activity as well as clonogenic capability of murine CALM-AF10 AML cells."
31022428
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"Pharmacological BMI1 inhibition impairs human CALM-AF10 AML in vitro and in vivo ."
31022428
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"In summary, our results demonstrate that BMI1 is a bona fide candidate for therapeutic targeting in AML with CALM-AF10 rearrangements and possibly other leukemias with CALM-AF10 rearrangements."
31022428
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"The fact that elevated BMI1 expression is a common feature of CALM-AF10 leukemias regardless of lineage suggests that BMI1 may be a transcriptional target of the CALM-AF10 fusion protein."
31022428
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"We transduced these cells or their Bmi1 wild-type counterparts with a retroviral expression vector encoding a highly oncogenic version of the CALM-AF10 fusion oncogene ( xref ) along with a bicistronic TdTomato fluorescent reporter."
31022428
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"These results indicate that Bmi1 is required for the immortalization of murine hematopoietic cells by the CALM-AF10 fusion gene."
31022428
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"We then sought to determine whether hematopoietic cells already transformed by CALM-AF10 are also sensitive to Bmi1 deletion."
31022428
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"We immortalized HSPCs from these Bmi fl/fl mice with the CALM-AF10 fusion gene."
31022428
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"We observed that CALM-AF10 transduced cells showed a significant decrease in their ability to form undifferentiated, blast-like colonies (see xref ), upon loss of Bmi1 alleles, while differentiated colony formation was not significantly impaired ( xref )."
31022428
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"We then performed in vitro proliferation as well as CFU assays from CALM-AF10 transformed bone marrow cells treated with 4-OHT or vehicle control (DMSO)."
31022428
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"Taken together, these experiments, using Bmi1 constitutive or conditional knockout-mice, revealed that Bmi1 is critical for the initiation as well as maintenance of transformation by the CALM-AF10 fusion oncogene."
31022428
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"Small-molecule BMI1 inhibition impairs murine CALM-AF10 AML growth and survival."
31022428
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"We examined the effect of PTC-209 on mouse CALM-AF10 AML cell-growth by treating primary AML cells from three independently derived tumors."
31022428
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"The fusion genes with similar mechanism include CALM-AF10 and MLL-AF10 ( xref ), which can lead to the H3K79 hypermethylation of HOXA genes and mediate the occurrence of leukemia."
37909026
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"We observed that PTC-209 induced a highly significant and concentration-dependent decrease in the number of viable CALM-AF10 AML cells over time ( xref ) in comparison to their vehicle-treated counterparts."
31022428
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"The sensitivity of CALM-AF10 AML cells to PTC-209 was in the low micromolar range with an EC 50 of 1.9 μM ( xref )."
31022428
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"As a result of small-molecule library screening, it was observed that small-molecule CCI-007, although not specific for MEIS1, had a cytotoxic effect within few hours in CALM-AF10, MLL-r, and SET-NUP214 leukemia cell lines (Somers et al., 2016)."
33402862
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"Therefore, it is also likely that the CALM-AF10 fusion-event drives enhanced BMI1 expression through the disruption of topologically associated domains (TADs) and juxtaposition of BMI1 to the strong, CALM-associated enhancers, as a result of the t(10;11) translocation."
31022428
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"A gene test of 11 fusion gene positive T-ALL patients by Ben et al ( xref ). showed that none of the 11 patients expressed CALM-AF10 , SIL-TAL , TLX1 or TLX3 (0/11,0%)."
37909026
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"In CALM-AF10, the clinical rationale for BMI1 targeting may be clearer, given that BMI1 is strongly upregulated in CALM-AF10 rearranged AML."
31022428
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"Our observation that CALM–AF10 fusions require BMI1 for initiation as well as maintenance of transformation provides pre-clinical evidence that pharmacological BMI1 inhibition may provide potential clinical benefit in leukemias with CALM-AF10 rearrangements."
31022428
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"It is pertinent to note that BMI1 upregulation is observed not only in CALM-AF10 positive AML, but also in T-ALL, where elevated BMI1 expression was first noted ( xref )."
31022428
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"Gene MLL Species H, M H, M Disease Leukemia (AML, ALL, MLL) Acute myeloid leukemia (AML) Genetic aberration/aberrant expression >50 different MLL fusions MLL-PTD References Reviewed in Ref. [29] [72,73,135] MLL2 H Hepatocellular carcinoma (HCC) M Acute myeloid leukemia (AML) Hepatitis B virus integration into MLL2: HBx-MLL2 fusion NUP98-JARID1A [136] [69] MLL3 H Colorectal cancer Intragenic mutations [22] DOT1L H, M M H, M Leukemia (AML, ALL) T-cell acute lymphoblastic leukemia (T-ALL) T-cell acute lymphoblastic leukemia (T-ALL) MLL-AF10 fusion, MLL-AF4 fusion CALM-AF10 fusion SET-NUP214 fusion [60,65] [61] [137] EZH2 H H H H H H, M H H H Bladder carcinoma Breast cancer Colorectal cancer (CRC) Gastric cancer Hepatocellular carcinoma (HCC) Lymphoma Melanoma Prostate cancer Various other cancers Overexpression: reduced miR-101, gene amplification Overexpression: gene amplification Overexpression: gene amplification Overexpression Overexpression Overexpression: reduced miR-26a, gene amplification Overexpression Overexpression: reduced miR-101 mediated repression Overexpression [13,17,99,138,139] [13,15,16,95] [13,140] [38] [141] [13,100,142,143] [95] [14,39,95] [13,95] NSD1 NSD2 NSD3 H, M H H H H H H H H Acute myeloid leukemia (AML) Myelodysplastic syndrome (MDS) Sotos syndrome Glioblastoma multiform (GBM) Hepatocellular carcinoma (HCC) Leukemia Multiple myeloma (MM) Various other cancers Acute myeloid leukemia (AML) t(5;11)(q35;p15.5) translocation: NUP98–NSD1 fusion t(5;11)(q35;p15.5) translocation: NUP98–NSD1 fusion Intragenic mutations; 5q35 microdeletions Overexpression Overexpression Overexpression t(4;14)(p16;q32): altered expression of FGFR3, NSD2 Overexpression t(8;11)(p11.2;p15) translocation: NUP98–NSD3 fusion [30,68,82] [31] [24,83,144,145] [146] [147] [91] [33,84–86] [18] [32] SUV39H1/2 EHMT1 SETDB1 M H H H H B-cell lymphoma 9q subtelomeric deletion syndrome Breast cancer Medulloblastoma Huntington’s disease (HD) Knockout mice Haploinsufficiency of EHMT1 Intragenic mutations Downregulation Overexpression [46] [27,148–150] [22] [151] [152] SMYD2 SMYD3 SMYD4 H H H H H H Hepatocellular carcinoma (HCC) Breast cancer Colorectal carcinoma (CRC) Hepatocellular carcinoma (HCC) Breast cancer Medulloblastoma Overexpression Overexpression Overexpression Overexpression Downregulation Downregulation [26] [153,154] [155] [155] [156] [151] PRDM1 PRDM2 PRDM5 PRDM12 PRDM14 H H H M H H H, M H H H H H H H Lymphoma Breast cancer Colorectal cancer (CRC) Diffuse B-cell lymphoma (DBCL) Gastric cancer Hepatocellular carcinoma (HCC) Lung cancer Neuroblastoma Breast cancer Colorectal and gastric cancer Liver cancer Ovarian cancer cell lines Chronic myeloid leukemia (CML) Breast cancer Mutations in PRDM1 gene; epigenetic silencing Mutations in PRDM2 gene; promoter DNA methylation Mutations in PRDM2 gene Knockout mice Mutations in PRDM2 gene; promoter DNA methylation Downregulation; promoter DNA methylation Downregulation; knockout mice Downregulation Downregulation; promoter DNA methylation Downregulation; promoter DNA methylation Downregulation; promoter DNA methylation Downregulation; promoter DNA methylation 9q microdeletions encompassing RRP4 and PRDM12 Overexpression [21,40–42] [20,34,157] [19,20] [158] [20,159] [36,160] [157,158] [157] [37] [38] [37] [37] [25,161] [162] PRMT1 CARM1 PRMT5 M H H H H Acute myeloid leukemia (AML) Breast cancer cell lines Breast cancer Prostate cancer Lymphoma and leukemia MLL-EEN fusion Overexpression Overexpression Overexpression Overexpression [70] [163] [164] [165,166] [167,168] M. Albert, K. Helin / Seminars in Cell & Developmental Biology 21 (2010) 209–220 213 several of the HMTs are important regulators of differentiation processes, one hypothesis is that misregulation of HMTs blocks normal differentiation and therefore contributes to tumor development."
19892027
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"Importantly, the synergy between the two drugs extent beyond MLL-AF9-driven malignancies and was also observed in those with CALM-AF10 (U937) and BCR-ABL (K562) fusions."
31408619
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"Leukemia transformed by the CALM-AF10 chromosomal translocation is characterized by a high incidence of extramedullary disease, central nervous system (CNS) relapse, and a poor prognosis."
35070954
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"The cytokines and cytokine receptors that play key roles in CALM-AF10 driven leukemia are unknown."
35070954
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"We find high cell surface expression of the cytokine receptor CXCR4 on leukemia cells expressing the CALM-AF10 oncogenic protein, contributing to the migratory nature of this leukemia."
35070954
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"Our discovery of altered cytokine receptor expression and function provides valuable insight into the propagation and persistence of CALM-AF10 driven leukemia."
35070954
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"Even though CALM-AF10 fusions are more frequent in T-ALL than in AML, CALM-AF10 mouse models reported so far are biased towards the myeloid lineage ( xref ; xref ; xref ; xref ), hampering the validation of therapeutic candidates for CALM-AF10 positive T-ALL."
31022428
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"Future studies will focus on the development of CALM-AF10 T-ALL models and the validation of BMI1 inhibitors in these studies."
31022428
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"Haploinsufficiency of CALM, as is found in cells expressing CALM-AF10, results in decreased endocytic efficiency ( xref )."
35070954
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"The NES is retained in the CALM-AF10 fusion construct, where it facilitates nucleocytoplasmic shuttling, and is necessary for leukemogenesis ( xref )."
35070954
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"Upregulation of HOXA genes in CALM-AF10 leukemias is a driving factor in CALM-AF10 mediated leukemogenesis ( xref , xref )."
35070954
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"Consistent with our chromatin studies, a recent report demonstrated that the small-molecule MYST HAT inhibitor WM-1119 can displace KAT6A::TIF2 or CALM::AF10 from chromatin in HEK293 cells ( xref , xref )."
40536430
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"We found that CALM-AF10 translocated U937 cells demonstrated an increase in cell migration upon stimulation with CXCL12, whereas the CALM-AF10 negative Kasumi-1 cells did not have a significant change in cell migration with the addition of CXCL12."
35070954
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"When analyzing the effects of a CXCR4 inhibitor, we found that AMD3465 treatment decreased the migration of CALM-AF10 translocated leukemias."
35070954
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"These observations indicate that AMD3465 exerts an inhibitory effect on migration of CALM-AF10 expressing leukemia cells."
35070954
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"3.2 Increased Expression of CXCR4 in CALM-AF10 Leukemia."
35070954
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"We assessed CXCR4 expression in U937 and Fujioka, two myeloid leukemia cell lines containing the CALM-AF10 translocation, and compared it with that in Kasumi-1, a myeloid leukemia cell line that does not express CALM-AF10 ."
35070954
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"Consistent with the elevated transcript levels, total CXCR4 protein was also increased in CALM-AF10 -translocated cell lines ( xref )."
35070954
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"Immunofluorescence microscopy further revealed that CXCR4 was primarily localized at the plasma membrane, to a greater degree in CALM-AF10 translocated leukemias ( xref )."
35070954
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"Murine embryonic fibroblasts (MEFs) were stably infected with CALM-AF10 or an empty vector ( xref ), and scratch assays were performed to assess the impact of the CALM-AF10 fusion oncoprotein on cell migration."
35070954
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"The CALM-AF10 transformed MEFs showed a 35 percent wound closure at 4 hours, compared to 19% closure in the empty vector cells (p<0.05)."
35070954
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"This difference was magnified at the 8-hour time point, with CALM-AF10 transformed cells showing a 85% closure, compared with 61% in the empty vector cells (p=0.04) ( xref )."
35070954
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"We then examined the migratory behavior of human leukemia cell lines and sought to identify cytokines that could be involved in the migration of CALM-AF10 leukemias."
35070954
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"Because CXCL12 is the primary ligand for the CXCR4 receptor, we investigated the migratory behavior of CALM-AF10 translocated leukemias when treated with CXCL12."
35070954
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"4.1 CALM-AF10 Transformed Cells Exhibit Enhanced Cell Migration."
35070954
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"The t(10;11)(p13;q14-21) chromosomal translocation encodes the leukemogenic CALM-AF10 fusion oncoprotein."
35070954
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"The CALM-AF10 translocation is found in both acute myeloid and acute lymphoid leukemias and are found most frequently in T-ALL at an incidence of about 15%."
35070954
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"CALM-AF10 leukemia is driven by overexpression of HOX homeobox cluster genes ( xref , xref )."
35070954
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"The upregulation of HOXA genes in CALM-AF10 leukemia is dependent on AF10’s recruitment of DOT1L, and resultant focal H3K79 hypermethylation specifically at the HOXA locus ( xref , xref )."
35070954
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"CALM-AF10 also interacts with the CRM1/XPO1 nuclear export receptor via CALM’s nuclear export signal peptide sequence, which is retained in the fusion protein, and is necessary for leukemogenesis."
35070954
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"This interaction is required for localization of CALM-AF10 to the HOXA cluster, and for resultant HOXA overexpression ( xref )."
35070954
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"The PHD1-zinc-knuckle-PHD2 (PZP) domain of AF10 is consistently interrupted in CALM-AF10 translocations."
35070954
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"It has been recently identified that the disruption of the PZP domain of AF10 disrupts the normal localization of DOT1L across the genome, allowing DOT1L to be tethered to the HOXA locus by CALM-AF10 ( xref )."
35070954
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"We determined the CXCR4 expression in secondary murine cell line models, characterized by either CALM-AF10 or Hoxa9-Meis1 chromosomal translocations, to further validate the relationship between CALM-AF10 and increased CXCR4 expression in human AML cell lines."
35070954
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"We investigated whether the increased cell migration we observed in CALM-AF10 transformed cells correlated with CXCR4 expression."
35070954
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"Following the discovery that CALM-AF10 expressing leukemia cells migrate toward a CXCL12 stimulus, we tested whether blocking this interaction could halt migration."
35070954
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"Consistent with this finding, we found an increase in CXCR4 expression specifically in human leukemia cell lines carrying the CALM-AF10 translocation."
35070954
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"These are all sites of potential leukemic involvement, with extramedullary involvement being characteristic of CALM-AF10 leukemias ( xref )."
35070954
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"It is possible that high CXCR4 expression on the plasma membrane of CALM-AF10 leukemias contributes to the development of extramedullary disease."
35070954
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"Additional in vivo studies are needed to definitively establish the relationship between CXCR4 expression and extramedullary disease development in CALM-AF10 leukemia."
35070954
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"4.3 The Effect of CXCR4 Inhibition on CALM-AF10 Leukemia Cells."
35070954
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"The studies presented here are limited by the use of cell lines, and future studies examining CXCR4 expression and the use of CXCR4 inhibitors in patient samples will add valuable insight to the biology of CALM-AF10 leukemia."
35070954
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"Additional studies are needed to establish whether CXCR4 inhibition impacts other characteristics of CALM-AF10 leukemia, including CNS invasion."
35070954
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"In this study, we demonstrate that CALM-AF10 translocated leukemias show an increased expression of CXCR4, as well as an increase in CXCL12-stimulated cell migration."
35070954
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"Acute leukaemia with a PICALM-MLLT10 fusion gene (originally called CALM-AF10 ) is generated by t(10;11)(p12-13;q14-21) translocation, and has been very rarely reported in patients with T-ALL, at an overall rate of 10%, including both adults and children [ xref ]."
33467425
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"In vitro, CTCF knockout (KO) reduced the colony‐forming capacity of CALM‐AF10 AML cells and induced their differentiation into macrophage‐like cells."
40875517
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"Knockdown of Tgm2 using short hairpin RNA (shRNA) in CALM‐AF10 AML cells and in the human leukemic cell line U937 harboring the CALM‐AF10 fusion gene resulted in reduced colony formation and proliferation."
40875517
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"We report the novel findings that despite an intact CXCR4 signaling pathway, CALM-AF10 carrying leukemia cells do not show additive nor synergistic cytotoxic or anti-proliferative effects upon combinatorial inhibition of CXCR4 and traditional chemotherapeutics."
35070954
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"We searched PubMed for possible spellings of the translocation of interest (“ PICALM-MLLT10 ”, “ CALM-AF10 ”, “ PICALM::MLLT10 ”, “ CALM::AF10 ”) alone and in combination with “AML” or “Acute myeloid leukemia”."
40983660
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"These findings suggest that CTCF regulates TGM2 expression by modulating post translational modifications of histones at its TSS, thereby preserving the undifferentiated state of CALM‐AF10 AML cells."
40875517
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"U937 harbors a t (10;11) (p13; q14) translocation resulting in the CALM-AF10 fusion gene."
33999861
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"Standard chemotherapeutic strategies are often ineffective in treating patients with MLL-AF9 and CALM-AF10 fusions [ xref ]."
33999861
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"CALM‐AF10 fusion gene‐induced AML (CALM‐AF10 AML), caused by the t (10;11)(p13;q14) translocation, is classified as a high‐risk subtype [ xref , xref ]."
40875517
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"In our study, we demonstrated the critical role of CTCF in the development of CALM‐AF10 AML."
40875517
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"Moreover, we identified TGM2 as a novel target gene regulated by CTCF and established that the enzymatic activity of TGM2 is essential for sustaining CALM‐AF10 AML."
40875517
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"Hematopoietic stem and progenitor cells (HSPCs) isolated from these mice were transduced with the CALM‐AF10 fusion gene and analyzed in both in vivo and in vitro models."
40875517
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"Further, recent studies proposed a model where the YEATS domain within the MOZ/ENL complex is needed for recruitment of AF10 fusion proteins (MLL-AF10, CALM-AF10 and others) to the HOXA gene cluster, critical for leukemogenesis[ xref ]."
37295550
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"To further investigate the role of TGM2 in CALM‐AF10 AML, we performed Tgm2 knockdown (KD) using shRNA in CALM‐AF10 AML cells."
40875517
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"Tgm2 KD significantly inhibited the colony‐forming ability of CALM‐AF10 AML (Figure  xref )."
40875517
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"MLL and CALM are believed to translocate with the AF10 gene to produce fusion proteins MLL/AF10 and CALM-AF10, respectively, which are closely associated with the occurrence of acute leukemia ( xref ; xref )."
37435030
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"Patients with CALM-AF10 + acute leukemia were previously found to typically have poor prognoses ( xref , xref , xref ), but this finding was mainly based on sporadic reports and had not been evaluated in prospective clinical trials of ALL or AML ( xref , xref , xref )."
35117001
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"Indeed, subsequent studies found no difference in the 3-year EFS and OS between the CALM-AF10 + and CALM-AF10 − groups ( xref )."
35117001
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"Based on the pathogenic mechanism of leukemia induced by CALM-AF10 ( xref ), it is proposed that nuclear export inhibitors be included in the treatment of CALM-AF10 + leukemia ( xref , xref )."
35117001
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"In addition, CALM-AF10 + leukemia cells are more sensitive to iron-restricted growth inhibition than normal hematopoietic cells, and the tumor burden in the spleen appears to be reduced by dietary iron restriction ( xref , xref )."
35117001
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"However, whether the iron depletion strategy improves the prognosis of CALM-AF10 + leukemia patients has not been verified."
35117001
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"In addition, Fluorescence Activated Cell Sorting (FACS) analysis confirmed the increased expression of CD68 and F4/80, key markers of macrophage differentiation, in Ctcf ‐deficient CALM‐AF10 AML cells (Figure  xref )."
40875517
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"Collectively, these findings demonstrate that CTCF is indispensable for both the initiation of leukemogenesis and the preservation of an undifferentiated state in CALM‐AF10 AML cells."
40875517
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"To identify genes regulated by CTCF that are crucial for maintaining the undifferentiated state of CALM‐AF10 AML cells, RNA sequencing (RNA‐seq) was performed following Ctcf KO."
40875517
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"Together, our findings demonstrate a key role of AF10 PZP in blocking leukemic transformation by CALM-AF10 through both in cis and in trans mechanisms."
34226546
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"We report an increase in cell surface expression of CXCR4, and a concomitant increase in the migratory behavior of cells transformed by CALM-AF10 ."
35070954
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"Using both human and mouse cell line models, we examine the relationship between CXCR4 expression and phenotype in CALM-AF10 transformed leukemias."
35070954
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"3.1 Enhanced Cell Migration in CALM-AF10 Transformed Cells."
35070954
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"We performed ChIP-seq experiments using in trans leukemia repression system, in which CALM- PZP AF10 MF was overexpressed in CALM-AF10 MF leukemia cells (Fig.  xref )."
34226546
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"Furthermore, the incorporation of AF10 PZP caused the spreading of H3K79me2 genome-wide beyond the H3K79me2-enriched sites in CALM-AF10 MF leukemia cells (Fig.  xref )."
34226546
sparser
"We note that most of the increase in H3K79me2 levels was found at promoter-proximal regions of genes, including those that are not CALM-AF10 targets (Figs.  xref b and xref )."
34226546
sparser
"The CALM-AF10 fusion is believed to play a role in targeting DOT1L to gene loci, which results in the deposition of H3K79 methylation and transcriptional activation."
34226546
sparser
"We, therefore, examined whether the inclusion of AF10 PZP in CALM-AF10 can lead to changes in H3K79 methylation in CALM-AF10 leukemia cells."
34226546
sparser
"These findings suggest that CTCF maintains the undifferentiated state of CALM‐AF10 AML cells by regulating Tgm2 expression."
40875517
sparser
"So far, 326 Gasparini et al. TABLE I. Recurrent Balanced Rearrangements in Hematological Malignancies Hemapoietic tumors Lymphoid Disease Anaplastic large cell lymphoma Burkitt’s lymphoma, B-cell ALL B-cell precursor acute lymphoid leukemia Diffuse large B-cells lymphoma Extranodal mucosa-associated lymphoid tissue Plasma cells myeloma Pre-T cell lymphoblastic leukemia, lymphoma Acute promyelocytic leukemia Acute myeloid leukemia or CMML Acute myeloid leukemia Affected gene NPM-ALK TPM3-ALK TFG-ALK ATIC-ALK MSN-ALK CLTCL-ALK MYC (relocation of IgH locus) MYC (relocation of IgK locus) MYC (relocation of IgL locus) E2A-PBX1 E2A-HLF TEL-AML1 BCR-ABL MLL-AF4 IL3-IgH BCL2-IgH BCL6-variant partners BCL8-IgH FCGR2-Igl MUC1-IgH NFKB2-IgH MALT1-API2 MALT1-IgH BCL10-IgH BCL10-Igk FGFR3-IgH and MMSET MAF-IgH MAF-Igl CCND1-IgH MUM/IRF4-IgH MYC (Relocation to TCR a/d locus) LYL1 (Relocation to TCRB locus) TAL2 (Relocation TCRb locus) SCL (Relocation to TCR a/d locus) OLIG2 (Relocation to TCR a/d) LMO1(RBTN1) (Relocation to TCR a/d) LMO2 (RBTN2) (Relocation to TCR a/d) HOX11 (Relocation to TCR a/d) HOX1 – 1L2 CALM-AF10 NUP98-RAP1GDS1 Myeloid PML-RARa NPM-RARa PLZF-RARa ETV6-variant partners NUP98-variant partners MLL-variant partners AML1-ETO CBFB-MYH11 FUS-ERG CEV14-PDGFRB P300-MOZ MOZ-TIF2 MOZ-CBP DEK-NUP214 RBM15-MKL MLF1-NPM1 AML1-EVI1 Rearrangement t(2;5)(q23;q35) t(1;2)(q25;p23) t(2;3)(p23;q21) inv(2)(p23q35) t(X;2)(q11 – 12;p23) t(2;17)(p23;q23) t(8;14)(q24;q32) t(2;8)(p12;q24) t(8;22)(q24;q11) t(1;19)(q23;p13) t(17;19)(q22;p13) t(12;21)(p12;q22) t(9;22)(q34;q11.2) t(4;11)(q21;q23) t(5;14)(q31;q32) t(14;18)(q32;q21) t(3;v)(q27;v) t(14;15)(q32;q11 – 13) t(1;22)(q22;q11) t(1;14)(q21;q32) t(10;14)(q24;q32) t(11;18)(q21;q21) t(14;18)(q32;q21) t(1;14)(p22;q32) t(1;2)(p22;p12) t(4;14)(p16;q32) t(14;16)(q32;q23) t(16;22)(q23;q11) t(11;14)(q13;q32) t(6;14)(p25;q32) t(8;14)(q24;q11) t(7;19)(q35;p13) t(1;14)(p32;q11) t(14;21)(q11;q22) t(11;14)(p15;q11) t(11;14)(p13;q11) t(10;14)(q24;q11) t(5;14)(q35;q32) t(10;11)(p13;q21) t(4;11)(q21;p15) t(15;17)(q21;q21) t(5;17)(q35;q21) t(11;17)(q23;q21) t(12;v)(p13;v) t(11;v)(p13;v) t(11;v)(q23;v) t(8;21)(q22;q22) inv(16)(p13q22) t(16;21)(p11;q22) t(5;14)(q33;q32) t(8;22)(q33;q32) inv(8)(p11q13) t(6;9)(p23;q34) t(1;22)(p13;q13) t(3;5)(q25;q34) t(3;21)(q26;q22) Chromosomal Alterations in Cancer Development 327 Fig. 2."
17722107
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"35 It has been reported that CALM-AF10 can enhance the expression of HOXA5 by the regulation of H3K79 methylation, 36 which plays important roles in leukemogenesis."
33223227
sparser
"The fusion of CRM1-AF10 has been noted to activate the HOXA gene cluster in T-ALL, in a similar manner to CALM-AF10, which requires CRM1 for HOXA gene activation [ xref ]."
39161560
sparser
"Intriguingly, in this study and others, CRM1 was found to localize to the HOXA gene cluster in CALM-AF10 and NUP98-HOXA9 fusion leukemias, highlighting its role outside of nuclear export and involvement with DNA and chromatin [ xref ]."
39161560
sparser
"Of interest, increased H3K79 methylation levels by enhanced DOT1L activity are also observed in CALM-AF10 fusion leukemias resulting in upregulation of HOXA5 ( Lin et al., 2009; Okada et al., 2006 )."
24786297
sparser
"It is not known whether the CALM portion of CALM-AF10 can target AF10 and consequently DOT1L to distinct genomic loci."
25592767
sparser
"Similar to the role played by Crm1 in CALM-AF10 leukemogenesis [ xref ], we propose that Crm1 enables the recruitment of NUP fusion proteins to the regulatory regions of Hoxa genes."
32343715
sparser
"Thus, the mechanism by which CALM-AF10 fusion-positive leukemias exhibit a transcriptional profile that resembles that of MLL1 translocated leukemias is not known."
25592767
sparser
"It has not been demonstrated that the KMT2A-menin complex is involved in the process by which CALM-AF10 upregulates HOXA genes."
41350360
sparser
"As expected, 5’SE mutations, and SIL-TAL1 were both mutually exclusive with other major T-ALL driver oncogenes such as TLX1, TLX3, CALM-AF10 (Supplementary Tables xref  and xref ) [ xref , xref ]."
36650499
sparser
"One patient with CALM-AF10 AML achieved complete remission (CR) following treatment with the menin inhibitor enzomenib (the details of this agent will be discussed in the following section) xref ."
41350360
sparser
"The CALM-AF10 translocation was first identified in a patient with histiocytic sarcoma but is more commonly seen in T acute lymphoblastic leukemia (T-ALL), where it makes up about 15% of pediatric and adult cases ( xref – xref )."
35070954
sparser
"AF10 PZP promotes nuclear localization of CALM-AF10 and is required for association with chromatin."
34226546
sparser
"Treatment with GK921 significantly reduced the growth of CALM‐AF10 AML cells and promoted their differentiation into macrophage‐like cells, demonstrating that the enzymatic activity of TGM2 is essential for maintaining the undifferentiated state (Figure  xref )."
40875517
sparser
"Future studies should further explore the mechanisms underlying CTCF‐mediated recruitment of histone‐modifying enzymes and investigate the clinical applicability of TGM2 inhibitors in treating CALM‐AF10 AML, with a particular focus on determining the therapeutic range."
40875517
sparser
"Recurrent genetic abnormalities were observed in 4 patients (30.8%), including KMT2A rearrangement (2 cases), EVI1 rearrangement (1 case), and CALM-AF10 fusion (1 case)."
41540127
sparser
"The fact that CATS modulates the CALM/AF10 transactivation capacity suggests that the CATS-CALM/AF10 (and possibly CATS-KIS) interaction is important for leukemogenesis."
23419774
sparser
"The major genetic classes of T-ALL involve TLX1/3, TAL1/SCL, LMO1/2, LYL1, CALM-AF10, SET-NUP214, and NOTCH1 as defined by chromosomal translocation or over/contextually inappropriate expression xref ."
31266935
sparser
"PICALM - MLLT10 , formerly CALM-AF10 , is a rarely reported fusion gene in hematological malignancies, especially in Asian people."
39499083
sparser
"The CALM-AF10 t(10;11)(p12;q14) translocation is particularly highly leukemogenic and is linked to aggressive acute leukemias."
34226546
sparser
"It has been shown that PZP of AF10 engages the nucleosome through multivalent interactions with the entire H3 tail as well as DNA and that incorporation of functional PZP in leukemogenic CALM-AF10 fusions blocks the transforming activity in vitro and in vivo and abolishes CALM-AF10–driven leukemogenesis in vivo ( xref )."
36907441
sparser
"The compound also significantly inhibited growth of leukemia cell lines with a CALM-AF10 translocation, which defines a highly aggressive leukemia subtype that shares common underlying leukemogenic mechanisms with KMT2A-r leukemia."
35127484
sparser
"Our data indicate that the disruption of AF10 PZP function in the CALM-AF10 fusion directly leads to transformation, whereas the inclusion of AF10 PZP downregulates Hoxa genes and reverses cellular transformation."
34226546
sparser
"Apart from the NUP98 fusions, Hox gene dysregulation has also been associated with MLL fusions, the CALM-AF10 fusion, and NPM1 and IDH1 mutations in leukemia [ xref , xref , xref , xref ]."
32993115
sparser
"Incorporation of functional AF10 PZP into the leukemogenic CALM-AF10 fusion prevents the transforming activity of the fusion in bone marrow-derived hematopoietic stem and progenitor cells in vitro and in vivo and abrogates CALM-AF10-mediated leukemogenesis in vivo."
34226546
sparser
"Thus, SID7969543 represents a novel candidate agent with selective activity against CALM-AF10 translocated and KMT2A-r leukemias that warrants further investigation."
35127484
sparser
"As shown in Fig.  xref (middle panel), expression of CALM-AF10 MF in bone marrow-derived HSPCs led to the formation of a large number of colonies with an undifferentiated, blast-like morphology, confirming the potent transforming ability of the CALM-AF10 MF fusion xref ."
34226546
sparser
"The ability of CALM- PZP AF10 MF to reverse the potent transformed phenotype of the CALM-AF10 MF fusion indicates that AF10 PZP has a trans-dominant tumor-suppressive function over the CALM-AF10 MF fusion."
34226546
sparser
"We identified SID7969543, an inhibitor of transcription factor Nuclear Receptor Subfamily 5 Group A Member 1 (NR5A1), as a novel selective candidate inhibitor against a subset of KMT2A-r and CALM-AF10 translocated leukemia cells, including cells derived from infants with KMT2A-r leukemia."
35127484
sparser
"To determine the role of AF10 PZP in the leukemogenic activity of the CALM-AF10 translocation, we modified the CALM-AF10 chimera that was reported to cause potent malignant transformation of bone marrow-derived hematopoietic stem and progenitor cells (HSPCs) xref ."
34226546
sparser
"This chimera consists of the C-terminal part of CALM (aa 400–648, CALM CT ), encompassing the TAD domain and NES, fused with AF10 OMLZ (aa 677–758) and represents the minimal fusion construct (CALM-AF10 MF ) that induces transformation to the same extent as the original CALM-AF10 fusion (Fig.  xref ) xref ."
34226546
sparser
"Because CALM-AF10 MF does not contain AF10 PZP , we generated CALM- PZP AF10 MF by incorporating AF10 PZP ."
34226546
sparser
"We then transduced bone marrow-derived HSPCs with CALM-AF10 MF , CALM- PZP AF10 MF, or the MSCV-IRES-GFP (MIG) empty vector, purified transduced cells using a co-expressed fluorescence marker, and tested these cells in a methyl-cellulose-based semi-solid colony-forming unit (CFU) assay (Fig.  xref )."
34226546
sparser
"Furthermore, undifferentiated colonies from CALM-AF10 MF transformed cells gave rise to the blast-like colonies in secondary and tertiary replating experiments, whereas the colonies from MIG vector or CALM- PZP AF10 MF transduced cells had no serial replating capacity (Fig. xref )."
34226546
sparser
"These results suggest that the introduction of the AF10 PZP domain into the CALM-AF10 fusion abrogates the transforming ability of this chimera in vitro."
34226546
sparser
"We next tested CALM- PZP AF10 MF in the in vivo clonogenic colony-forming unit-spleen (CFU-S) assay, in which the CALM-AF10 MF fusion was shown to confer high CFU-S capability to bone marrow-derived HSPCs xref ."
34226546
sparser
"Bone marrow-derived HSPCs transduced with the CALM-AF10 MF fusion formed a median of 100 colonies per 50,000 injected cells (Fig.  xref )."
34226546
sparser
"We concluded that the incorporation of AF10 PZP impedes the ability of the CALM-AF10 MF fusion to form a high number of CFU-S colonies in vivo."
34226546
sparser
"The CALM-AF10 fusion is known to upregulate HOXA cluster genes and the HOX-cofactor MEIS1 , which is a hallmark of this subtype of leukemia."
34226546
sparser
"To further characterize the cytotoxic profile of the adenosine analog 2-Cl-ATP, the compound was evaluated in an expanded leukemia cell line panel comprising six additional KMT2A-r leukemia cell lines, including five derived from infants with KMT2A-r ALL and two CALM-AF10 translocated leukemias, which are KMT2A-wt but represent an aggressive leukemia subtype that shares underlying molecular etiological pathways with KMT2A-r leukemias, such as their dependency on DOT1L histone-lysine methyltransferase and an upregulation of  HOXA  cluster genes ( xref – xref )."
35127484
sparser
"To establish whether the inclusion of AF10 PZP can affect the in vivo leukemogenic activity of the CALM-AF10 translocation, we injected mice ( n  = 5 mice per arm) with HSPCs transduced with either the MIG empty vector control, the CALM-AF10 MF fusion gene, or the CALM- PZP AF10 MF fusion gene (Fig.  xref )."
34226546
sparser
"While the injection of bone marrow-derived HSPCs transduced with CALM-AF10 MF led to fully penetrant leukemias with a median of 93 days, none of the mice injected with CALM- PZP AF10 MF HSPCs developed disease up to 300 days post-transplantation."
34226546
sparser
"We used primary leukemia cells from mice with full-blown CALM-AF10 MF -induced leukemia and transduced these cells with the CALM- PZP AF10 MF fusion gene."
34226546
sparser
"Since the cells were from a primary AML, CALM-AF10 MF leukemia cells produced almost exclusively blast-like colonies in CFU assays."
34226546
sparser
"A considerable, ~5-10-fold downregulation of these genes observed in the cells transduced with CALM- PZP AF10 MF suggested that the CALM- PZP AF10 MF fusion can reverse Hoxa activation by the CALM-AF10 MF fusion oncoprotein."
34226546
sparser
"To determine the role of AF10 PZP in Hoxa gene expression, we transduced murine bone marrow-derived HSPCs with either the leukemia-associated CALM-AF10 fusion lacking the first 80 amino acids of AF10, including the first PHD finger (Fig.  xref , second schematic), or a CALM-AF10 fusion (CALM- full AF10) which contains full-length AF10 (1–1027 amino acids), including the entire PZP domain, and measured Hoxa transcript levels by qRT-PCR."
34226546
sparser
"CALM-AF10 expression in murine bone marrow-derived HSPCs led to a substantial increase in Hoxa7 , Hoxa9 , Hoxa10 , and Meis1 levels compared to the levels of these genes in CALM- full AF10 expressing cells, indicating that the exclusion of AF10 PZP may be necessary for HOX/MEIS activation by the CALM-AF10 fusion protein (Fig.  xref )."
34226546
sparser
"The compound also exerted significant inhibitory effects against both CALM-AF10 translocated leukemia cell lines when compared to other KMT2A-wt leukemia cell lines, the solid cancer cell lines and non-malignant cells ( xref and xref )."
35127484
sparser
"To explore whether incorporation of AF10 PZP affects Hoxa gene activation by CALM-AF10 in trans , we transduced CALM-AF10 MF leukemia cells with CALM- PZP AF10 MF and measured Hoxa transcript levels by qRT-PCR (Fig.  xref and Suppl."
34226546
sparser
"As expected, CALM-AF10 MF cells were characterized by a high expression of CALM-AF10 target genes Hoxa7 , Hoxa9 , Hoxa10 , and Meis1 (Fig.  xref )."
34226546
sparser
"These results also help to explain the fact that AF10 PZP is disrupted in all CALM-AF10 fusions, as analysis of the TARGET pediatric AML dataset pointed out that most of the leukemia-associated breakpoints in the AF10 gene in pediatric leukemias are located in or right after AF10 PZP , and a few more breakpoints are located just upstream of AF10 OMLZ , but importantly, in all these fusions AF10 PZP is impaired or excluded (Fig.  xref )."
34226546
sparser
"Similar to 2-Cl-ATP, all cell lines that were sensitive towards SID7969543 (IC 50 < 10 µM) were leukemias with either a KMT2A or CALM-AF10 translocation ( xref and xref )."
35127484
sparser
"SID7969543 decreased the viability of a subset (7/11) of KMT2A-r cells as well as both CALM-AF10 leukemia cells, with IC 50 values ranging from 1 µM to 5 µM, while not affecting the other KMT2A-wt leukemia cells, solid tumors or non-malignant cells ( xref and xref ; xref )."
35127484
sparser
"Moreover, we demonstrate that this selective sensitivity to nucleoside analogs can be extended to CALM-AF10 translocated leukemias."
35127484
sparser
"Additional transcription factors mutated in at least 5% of adult T-ALL cases include MYB, ETV6, WT1, RUNX1, BCL11B, CALM-AF10, MLL-ENL, CNOT3 and SET-NUP214."
31585620
sparser
"Our finding that SID7969543 also targets CALM-AF10 translocated leukemia cells, supports previous reports showing that KMT2A and CALM-AF10 translocations rely on common underlying leukemogenic pathways ( xref – xref ) and further emphasizes that both leukemia subtypes share common targetable vulnerabilities."
35127484
sparser
"This is in line with observations in our earlier studies that focused on large-scale chemical library screening and yielded novel candidate drug molecules with selectivity for KMT2A-r leukemia that were similarly cytotoxic against CALM-AF10 translocated leukemias ( xref , xref )."
35127484
sparser
"Overall, our results show that SID7969543 represents a novel candidate agent with selective activity against KMT2A and CALM-AF10 translocated leukemia, warranting further investigation."
35127484
sparser
"The transduction of mutant CALM‐AF10 cDNA in C57BL/6 mice bone marrow cells led to increased expression of lineage‐uncommitted progenitors in vitro . xref These cells did not express myeloid‐specific or lymphoid‐specific markers and displayed high levels of c‐kit."
33768878
sparser
"HOXA9 and MEIS1 are reportedly upregulated by DOT1L-mediated H3K79 methylation in aggressive leukemia driven by oncogenes, such as MLL-AF9, MLL-AF10, and CALM-AF10 ( Bernt et al., 2011; Chen et al., 2[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
32559496
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"At the molecular level, PICALM/AF10 induces the overexpression of HOXA cluster genes (particularly Hoxa5 ) through aberrant methylation of Lys79 of Histone 3 via DOT1L recruitment. xref Hoxa5 overexpression is critical but not essential for CALM‐AF10 ‐mediated leukemogenesis. xref In the Caudell et al study, xref CALM‐AF10 transgenic mice showed Hoxa5 overexpression, although they did not develop acute leukemia."
33768878
sparser
"AF10 PZP promotes nuclear localization of CALM-AF10 MF and is required for association with chromatin."
34226546
sparser
"To examine the role of AF10 PZP in the sub-cellular localization of CALM-AF10, we transfected Flag-tagged CALM-AF10 MF and CALM- PZP AF10 MF into HEK 293T cells and visualized the proteins by immunofluorescence (IF) using an anti-Flag antibody."
34226546
sparser
"IF analysis showed that while the CALM-AF10 MF fusion protein was predominantly cytosolic, in support of previous findings xref , xref , the CALM- PZP AF10 MF fusion protein accumulated largely in the nucleus (Fig.  xref )."
34226546
sparser
"Furthermore, CALM- PZPmut AF10 MF fusion protein, harboring D43K/E179K mutations that disrupt binding to H3 tail, lost its ability to accumulate in the nucleus and was found primarily in the cytosol, confirming the importance of functional AF10 PZP for the nuclear pool of CALM-AF10 (Fig.  xref , right panels)."
34226546
sparser
"In the absence of functional AF10 PZP within the leukemogenic fusion, CALM-AF10 can trap DOT1L at the Hoxa cluster, leading to the elevated local H3K79me2 level, constitutive activation of Hoxa genes, and a decrease in global H3K79me2 level due to the inability of the fusion to spread onto chromatin regions beyond the Hoxa loci (Fig.  xref , top)."
34226546
sparser
"Incorporation of the chromatin reader, AF10 PZP in the CALM-AF10 fusion allows for spreading onto other regions of chromatin, thus disseminating DOT1L to other sites in the genome."
34226546
sparser
"This mechanism sheds light on the aberrant stabilization of DOT1L at critical oncogenes and points to the CALM-AF10 fusion as a potential candidate for gene therapy aiming to eliminate the upregulation of oncogenes and reverse leukemogenesis."
34226546
sparser
"Alternatively, genetic defects including chromosomal deletions, fusion genes and somatic mutations have been identified that further define the different T-ALL subgroups including SIL-TAL1 deletions i[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
24786297
sparser
"Previously, we identified acquired mutations involving Ras ( Kras , Nras , Ptpn11 , Nf1, and Cbl ) or tyrosine kinase ( Flt3 , Kit , Jak , Stat , and Sh2b3 ) genes in 20–72% of leukemias driven by NUP98 fusion proteins or the related CALM-AF10 fusion protein [ xref , xref ]."
37147424
sparser
"Furthermore, the genetic diversity of T-ALL also includes chromosomal rearrangements (CALM-AF10, MiLL1-ENL, and NUP214-AFBL1), loss of transcription factors (e.g., LEF1, WT1, RUNX1, ETV6, etc.), cell cycle inhibitors (e.g., CDKN2A, RB and CDKN1B) and oncogene gains (e.g., MYB) [ xref ]."
36077822
sparser
"This mode of action is observed in MLL-fusion models but LSD1 inhibitors are much less active (µM range) in non-MLL cell models, even those over-expressing HOXA9, such as the U937 AML cell model (CALM-AF10 fusion)."
31213012
sparser
"The MOF inhibitor MG149 evidenced anti-leukemic activities of MLL-fused leukemia and other AML cell models that are associated with HOXA9 over-expression, such as the CALM-AF10 fusion model U937, but also the K562 cell model (BCR-ABL fusion) that does not express HOXA9 [ xref ], suggesting a more global epigenetic deregulation by MOF inhibitors that is not restricted to deregulated HOXA9 gene expression ( xref , point j ; xref )."
31213012
sparser
"Heterogeneous QKI expression has been shown in B-cell ALL, with QKI downregulation in pediatric subtypes of leukemia. xref MiR-155-dependent-QKI depletion has been implicated in inflammation in chronic lymphocytic leukemia. xref In T-ALL, QKI downregulation was reported in cases with high HOXA expression, carrying CALM-AF10 xref or KMT2A rearrangements. xref The QKI transcript displayed a highly heterogeneous level of expression in T-ALL (range, 0-15 transcripts per million) ( xref ), according to RNA-sequencing data in 25 pediatric patients xref representing five T-ALL molecular subtypes. xref Two groups of patients with normal (QKI_normal) and aberrantly low (QKI_low) QKI expression ( xref ) were defined by comparison with their normal counterparts, five thymocyte populations from two healthy donors including three CD34 + early maturation and two CD4 + CD8 + stages of the ab lineage. xref CircComPara2 12 identified 3,376 circRNA expressed in the T-ALL samples, with an average of five circular isoforms per gene, and 20 genes with at least 15 circular isoforms, including TASP1 and CASC15 , each with 30 circRNA."
39633556
sparser
"To further explore how CRM1 affects Hoxa regulation by CALM-AF10, we studied the direct binding of CALM-AF10 at Hoxa loci."
25027513
sparser
"Toward this end, U937 cells harboring CALM-AF10 other than MLL-AF9 and 293T cells were transfected with pCDH-vector, pCDH-WT SMYD3, or pCDH-F183A SMYD3."
40451434
sparser
"With all conditions optimized, we then performed parallel in vivo and in vitro screens using Cas9-expressing MV4-11 and U937 cell lines, as well as PDX16-01(CALM–AF10 fusion, NF1 , PHF6 , and TP53 mutations; xref )."
34531254
sparser
"Although PDX models with MLL fusions and a CALM–AF10 fusion were used in this study, it should be feasible to establish CRISPR-competent PDX models with different genetic backgrounds and thus extend our dependency discovery capacity to other high-risk subtypes of AML."
34531254
sparser
"Certainly, a previous study suggested that CALM-AF10, an NES-containing fusion protein found in immature acute myeloid and T-lymphoid malignancies, could be recruited to CRM1 (bound to transcription start site of HOXA9 and HOXA10 ) in an NES-dependent manner ( xref )."
31755865
sparser
"Mol Biol Cell 1999;10(8):2687–702. [63] Lin YH, Kakadia PM, Chen Y, Li YQ, Deshpande AJ, Buske C, et al. Global reduction of the epigenetic H3K79 methylation mark and increased chromosomal instability in CALM-AF10 positive leukemias."
19892027
sparser
"Experiments of retroviral insertional mutagenesis identified Zeb2 activation as a leukaemogenesis-collaborating event in CALM-AF10 transgenic mice [ xref ]."
30658474
sparser
"We found that interaction of CALM-AF10 with Hoxa loci was inhibited by both mutation of the NES motif and treatment with LMB."
25027513
sparser
"Expression of a CALM-AF10 fusion gene leads to Hoxa cluster overexpression and acute leukemia in transgenic mice."
19892027
sparser
"In addition, Caudell et al. showed that CALM–AF10 transgenic mice infected with retrovirus developed predominantly B-ALL, and some of these mice carried retroviral insertions within the first intron of Evi1 resulting in a marked upregulation of Evi1 [38]."
24828867
sparser
"The expression of SMYD3 in peripheral blood mononuclear cells (PBMCs) isolated from healthy donors, patients with AML, or AML cell lines harboring various fusion genes including MLL-AF9, MLL-AFF1, AML-ETO, and CALM-AF10 were examined by Western blotting analysis."
40451434
sparser
"In addition, Evi1 is targeted by a common insertion site discovered in retrovirally infected CALM–AF10 transgenic mice, which mostly develop B-lineage ALL [38]."
24828867
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"43 , 50 , 51 Moreover, CALM-AF10, another NES-containing leukemogenic fusion protein, is recruited to the HOX cluster via CRM1."
37516964
sparser
"This is particularly interesting with regards to the extended latency of CALM-AF10 mediated leukemogenesis, which suggests that additional genetic alterations are required for the development of leukemia [64]."
19892027
sparser
"To first test our experimental system, we selected two monocytic PDX models that tolerated stable Cas9 expression and can be passaged for a limited time in vitro (PDX 16-01 with a CALM-AF10 fusion and PDX 17-14 with a MLL-AF10 fusion; see also xref and extended information xref )."
35405016
sparser
"Both of these roles for CRM1 are exploited by interaction with the aberrant CALM-AF10 fusion protein, which drives leukemic transformation."
25027513
sparser
"Notably, a patient with CALM-AF10 fusion, a menin-sensitizing alteration, achieved CR [ xref ]."
40528227
sparser
"Notably, a recent study suggests that CALM-AF10 dramatically reduces DOT1L recruitment to chromatin, resulting in global H3K79 hypomethylation in CALM-AF10 expressing cells [63]."
19892027
sparser
"In contrast to MLL-AF10 transformed cells, HoxA9 is not expressed in CALM-AF10 cells, where HoxA5 appears to be critical for leukemic transformation."
19892027
sparser
"Here, we find that interaction of CALM-AF10 with the nuclear export receptor CRM1 is necessary for activating HOXA gene expression."
25027513
sparser
"We also show that CALM-AF10 binds HOXA loci, while mutation of the NES motif or treatment with LMB prevents this interaction."
25027513
sparser
"The t(10;11)(p12-13;q14-21) translocation leads to the formation of a PICALM::MLLT10 fusion gene previously designated as CALM::AF10."
38443661
sparser
"CALM-AF10 interacts with the nuclear export receptor CRM1 via a NES within aa 544–553 of CALM ( xref )."
25027513
sparser
"The expression of SMYD3 in AML appeared complicated because Kasumi-1 harboring AML-ETO , U937 harboring CALM-AF10 and HL-60 without a known fusion gene also exhibited an increased SMYD3."
40451434
sparser
"In our cohort study, CALM-AF10 was associated with an immature immunophenotype and poor outcome (p=0.005)."
16956820
sparser
"The other notable abnormalities in T-LBL/ALL include phosphatase and tensin homolog ( PTEN ) deletion, CALM-AF10 fusion, mutations of IL-7R , and CASP8AP2 deletion."
35118290
sparser
"The genetic abnormalities which are associated with good prognosis include chromosomal rearrangements involving TAL1 [t(1:14)], t(1:17), TALX1, HOXA (CALM-AF10), deletion CDKN2A/2B, mutation in NOTCH1 and those associated with poor prognosis include rearrangements of TLX3 and mutation involving EZH2 ( xref )."
35118290
sparser
"Recently, an increasing number of CALM and AF10 interacting proteins have been identified ( Archangelo et al., 2006; Debernardi et al., 2002; Forissier et al., 2007; Greif et al., 2008; Okada et al., [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
19383357
sparser
"The PICALM–MLLT10 fusion gene (originally designated CALM-AF10 ) is generated by the t(10;11)(p12-13;q14-21) translocation which is a rare but recurrent event observed in patients with undifferentiate[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
22871473
sparser
"The t(10;11)(p13;q14-21) PICALM::MLLT10 chromosomal translocation results in the production of the CALM-AF10 fusion oncoprotein and is a driver mutation in both acute myeloid and T-lymphoblastic leukemia."
41532548
sparser
"Nucleocytoplasmic shuttling of CALM-AF10 and its protein partners and impaired endocytosis at the plasma membrane further influence the leukemic phenotype."
41532548
sparser
"Patients were stratified based on the mutational status of TAL1, HOX11/TLX1, HOX11L2/TLX3 and CALM-AF10 genes."
21652011
sparser
"Interestingly, the fusion-proteins SET-NUP214 and CALM-AF10 were identified as specific to γδ T-ALL and were found to be associated with chemotherapy resistance and poor prognosis, respectively [ xref , xref ]."
| PMC
sparser
"Here, we showed that ENL and DOT1L were localized at the HOXA loci in a MOZ-dependent manner in the absence of the CALM-AF10 fusion (Fig.  xref )."
37031220
sparser
"As we have reported for CALM-AF10 leukemia [ xref ], CRM1-AF10 and CRM1Δ-AF10 blasts rarely expressed the pan-B lymphoid marker B220."
32733011
sparser
"Leukemic bone marrow blasts from CALM-AF10 , CRM1-AF10 or CRM1Δ-AF10 mice expressed similar levels of Hoxa and Meis1 transcripts ( xref )."
32733011
sparser
"Similarly to CALM-AF10, CRM1-AF10 and CRM1Δ-AF10 both stimulated expression of a Hoxa7-Luciferase reporter in transiently transfected HEK293T cells, and increased expression of endogenous Hoxa and Meis1 genes in stably transduced murine fibroblasts ( xref – xref )."
32733011
sparser
"We have demonstrated that a CRM1-AF10 fusion protein phenocopies CALM-AF10 in its ability to bind and activate Hoxa and Meis1 genes and to induce leukemia, supporting a model in which CRM1 enables the tethering of CALM-AF10 to Hoxa and Meis1 effector genes, thereby recruiting the AF10/DOT1L transcriptional complex and causing leukemia."
32733011
sparser
"We further showed that CRM1Δ-AF10, a fusion remarkably similar to that found in a T-cell leukemia patient, was superior to CRM1-AF10 in its ability to phenocopy CALM-AF10."
32733011
sparser
"Notably, although no studies have demonstrated that KMT2A or menin are involved in CALM-AF10-mediated HOXA gene upregulation, a patient with CALM-AF10 fusion AML achieved complete remission following treatment with the menin inhibitor."
41350360
sparser
"AF10 fusions, such as CALM-AF10, are generated via chromosomal translocations, causing malignant leukemia."
37031220
sparser
"The t(10;11)(p13;q14) chromosomal translocation generating the CALM-AF10 ( PICALM-MLLT10 ) fusion gene is found in 5–10% of T-cell acute lymphoblastic leukemias (T-ALL) and more rarely in acute myeloid leukemias (AML) [ xref ]."
32733011
sparser
"Similar to MLL-AF10, CALM-AF10 binds the regulatory region of HOXA genes and activates their transcription by recruiting the H3K79 histone methyltransferase DOT1L via an octapeptide-motif/leucine zipper (OM/LZ) domain within AF10 (also called Myeloid/Lymphoid or Mixed Lineage Leukemia, translocated to chromosome 10, MLLT10) [ xref ]."
32733011
sparser
"We have shown that CALM contains a Nuclear Export Signal (NES) that is both necessary and sufficient for leukemic transformation of murine hematopoietic progenitor cells by enabling the binding of CALM-AF10 to Hoxa genes [ xref , xref ]."
32733011
sparser
"These observations support the hypothesis that an essential contribution of the CALM moiety within CALM-AF10 is to bring CRM1 in proximity to AF10."
32733011
sparser
"The poor clinical outcome of CALM-AF10 -driven leukemia necessitates the need for better understanding of how the translocation affects the behavior of the disease so that novel targeted therapies may be developed."
35070954
sparser
"To determine whether CRM1 can substitute for CALM within the CALM-AF10 fusion, we examined the transforming properties of constructs encoding a chimeric CRM1-AF10 protein and a variant CRM1-AF10 fusion protein, CRM1Δ-AF10, that lacks the inhibitory 43 carboxy-terminal amino acid of CRM1; this construct mimics a fusion protein found in a leukemia patient ( xref ) [ xref ]."
32733011
sparser
"To study the transforming activity of CRM1-AF10 and CRM1Δ-AF10, we transduced hematopoietic progenitor cells (HPCs) and monitored their colony forming potential in a serial replating assay using CALM-AF10 as a positive control [ xref ]."
32733011
sparser
"In comparison, mice transplanted with CALM-AF10 transduced progenitors developed leukemia within 98 to 200 days (median survival 160 days) ( xref )."
32733011
sparser
"In our mouse model, we observed a slightly more aggressive disease with a form of CALM-AF10 (CALM 2091 AF10) that has a tendency to form macroscopic aggregates, regardless of cellular location, and could be shown to oligomerize by FRET analysis."
21706055
sparser
"Cell 2005;121(2):167–78. [61] Okada Y, Jiang Q, Lemieux M, Jeannotte L, Su L, Zhang Y. Leukaemic transformation by CALM-AF10 involves upregulation of Hoxa5 by hDOT1L. Nat Cell Biol 2006;8(9):1017–24. [62] Tebar F, Bohlander SK, Sorkin A. Clathrin assembly lymphoid myeloid leukemia (CALM) protein: localization in endocytic-coated pits, interactions with clathrin, and the impact of overexpression on clathrin-mediated traffic."
19892027
sparser
"The t(10;11) (p12;q14) is a recurring chromosomal translocation resulting in PICALM::MLLT10 (also known as CALM::AF10 ), a fusion gene found in acute myeloid leukemia (AML), ALL, and malignant lymphoma [ xref , xref , xref ]."
41584902
sparser
"Lin and colleagues further demonstrated that the presence of the CALM-AF10 fusion results in global H3K79 hypomethylation associated with decreased genomic stability (105) , possibly owing to the role[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
25592767
sparser
"CALM-AF10 was associated with early relapse."
17928886
sparser
"Int J Hematol 2012;96:806–809. [38] Caudell D, Harper DP, Novak RL, et al. Retroviral insertional mutagenesis identifies Zeb2 activation as a novel leukemogenic collaborating event in CALM-AF10 transgenic mice."
24828867
sparser
"PTC-596 significantly prolongs survival of mice injected with a human CALM-AF10 cell line in a xenograft assay."
31022428
sparser
"Patients harboring the CALM-AF10 fusion have a particularly poor prognosis ( xref ; xref )."
31022428
sparser
"A subset of acute myeloid and lymphoid leukemia cases harbor a t(10;11)(p13;q14) translocation resulting in the CALM-AF10 fusion gene."
31022428
sparser
"Additionally, UBE2J2 or UBE2K deletion increased venetoclax sensitivity even in the NOXA -null cells of multiple AML models, including another PDX-derived model cultured briefly in vitro (PDX16-01, with CALM-AF10 fusion, NF1 , PHF6 and TP53 mutations) (Fig.  xref and Supplementary Fig,  xref )."
38366087
sparser
"It induced complete and sustained remission in xenograft models of KMT2A-r and CALM-AF10 leukemia in mice, showing significant efficacy in preclinical studies xref ."
41350360
sparser
"These results indicated that CALM-AF10 transformed HPCs via ENL."
37031220
sparser
"Other studies have shown that CD2 negativity correlated with the immature T-cell receptor and TCRγδ T-ALL lineages, which are associated with the occurrence of the CALM-AF10 fusion gene and the TLX3/HOX11L2 and MLL(KMT2A) gene rearrangements, considered to be prognostically unfavorable [ xref , xref , xref ]."
33921074
sparser
"qPCR demonstrates that Setdb1 expression is reduced in murine MLL-AF9 and CALM-AF10 leukemias compared to normal HSPC, consistent with the patient sample data ( xref )."
31558673
sparser
"In addition, ChIP-qPCR analysis of HEK293T cell lines expressing various ENL constructs showed that wild-type ENL was associated with the promoter regions of HOXA5 and HOXA9 , similar to CALM-AF10 (Fig.  xref ), indicating that ENL can target these promoters."
37031220
sparser
"Standard chemotherapeutic strategies are often ineffective in treating patients with CALM-AF10 fusions."
31022428
sparser
"In summary, these results validate BMI1 as a bona fide candidate for therapeutic targeting in AML with CALM-AF10 rearrangements."
31022428
sparser
"Taken together, chromatin targeting by CALM-AF10 is mediated by the MOZ/ENL complex, whose complex formation depends on the YEATS domain."
37031220
sparser
"ENL, DOT1L, and MYST family KATs are required for CALM-AF10 leukemia cells."
37031220
sparser
"To examine whether ENL, DOT1L, and MYST family KATs are required for CALM-AF10 leukemia cell proliferation, we performed CRISPR/Cas9-mediated competition assays on murine and human leukemia cells."
37031220
sparser
"HBO1 is required for both CALM-AF10 and MLL-ENL, as it is generally required for the survival of leukemia stem cells xref , xref ."
37031220
sparser
"While H3K9me2 is detected at HoxA5 in wild-type bone marrow cells, CALM-AF10 transduced cells loose this mark and gain H3K4me3 and H3K79me2 associated with active transcription."
19892027
sparser
"Similarly, the proliferation of P31/FUJ, a human leukemia cell line harboring CALM-AF10 fusion, depended on ENL and DOT1L (Fig.  xref )."
37031220
sparser
"WM1119 treatment reduced the presence of ENL and its cofactors at these target genes, accompanied by a reduction of the ChIP signal of RNAP2 Ser5-P. This suggests that WM1119 displaces ENL from the target promoters and impairs AEP-mediated transcriptional activation in CALM-AF10 leukemia cells."
37031220
sparser
"A similar cooperative effect was seen on another leukemia cell line carrying CALM-AF10 fusion, termed KP-Mo-TS xref (Supplementary Fig.  xref )."
37031220
sparser
"One of these other partners, PICALM::MLLT10 (originally called CALM::AF10 ) is generated by the t(10;11)(p12-13;q14-21) translocation, and has been rarely reported in patients with AML, acute lymphoblastic leukemia (ALL, especially T-phenotype), and acute undifferentiated leukemia. xref , xref The PICALM::MLLT10 fusion gene has been associated with high relapse rates and poor prognosis in adult AML, xref however, data are lacking in children with AML harboring this translocation."
38306602
sparser
"Inhibition of MOZ/MORF-mediated acetylation induces dissociation of MOZ/ENL and CALM-AF10 complexes from target chromatin."
37031220
sparser
"From these results, we conclude that CALM-AF10 leukemia cells are uniquely dependent on the acetylation activity of MOZ/MORF KATs."
37031220
sparser
"Consequently, CALM-AF10 recruitment was reduced by WM1119 treatment (Fig.  xref )."
37031220
sparser
"The t(10;11)(p13;q14) translocation is a recurrent, balanced translocation observed in human leukemia, which gives rise to the CALM-AF10 fusion protein ( xref ; xref )."
31022428
sparser
"We tested the antitumor effects of the MOZ/MORF KAT inhibitor on CALM-AF10 leukemia cells in vivo."
37031220
sparser
"In contrast, the proliferation of normal human CD34 + cells was unaffected under the conditions where that of P31/FUJ cells was severely impaired (Fig.  xref ), suggesting that the combined inhibition of MOZ/MORF KATs and DOT1L KMT selectively induces differentiation of CALM-AF10 leukemia cells."
37031220
sparser
"We observed that patient samples with AF10-fusions, including both CALM-AF10 as well as MLL-AF10 fusions expressed significantly higher levels of BMI1 compared to non AF10-rearranged samples."
31022428
sparser
"Standard chemotherapeutic strategies are often not very effective in treating patients with CALM-AF10 fusions."
31022428
sparser
"Hence, there is an urgent need to identify molecular pathways dysregulated in CALM-AF10 positive leukemias which may lay the foundation for novel targeted therapies."
31022428
sparser
"In contrast, CALM-AF10 requires an intact YEATS domain of ENL that confers targeting ability to MOZ/MORF complexes, suggesting that emerging YEATS domain inhibitors may be highly effective against AF10 translocation-induced leukemia xref – xref ."
37031220
sparser
"Elevated BMI1 expression is observed in AML as well as T-acute lymphoblastic leukemia (T-ALL) with CALM-AF10 rearrangements ( xref ; xref )."
31022428
sparser
"Early clues regarding the oncogenic mechanisms of CALM-AF10 came from transcriptome profiling studies using microarrays in AML and T-ALL."
31022428
sparser
"This decrease of the MOZ/ENL complex induces the dissociation of CALM-AF10 from the target chromatin."
37031220
sparser
"Towards this end, we utilized a well-established model of retroviral CALM-AF10 overexpression in murine hematopoietic stem and progenitor cells (HSPCs) ( xref )."
31022428
sparser
"DOT1L prevented nuclear export of the leukemic fusion protein CALM-AF10 and contributed to the upregulation of HoxA5 in leukemic cells."
19892027
sparser
"In fact, BMI1 overexpression has been associated with T-cell lymphomagenesis xref ; whole exome sequencing served to identify BMI1 mutations in early T-cell precursor-ALL xref and CALM-AF10  + T-ALL expression profiles revealed over-expression of this gene xref ."
30914738
sparser
"Further, specific immature subtypes characterized by aberrant HOXA gene activation, including SET-NUP214 - and CALM-AF10 -positive leukemias, were associated with higher levels of corticosteroid resis[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
26123366
sparser
"CALM-AF10 translocated T-ALL is characterized by the presence of extramedullary disease, CNS relapse, and poor response to therapy ( xref )."
35070954
sparser
"The small molecule CCI-006 was described as a novel inhibitor of mixed lineage leukemia (MLL)-rearranged, and CALM-AF10 translocated myeloid leukemia cells by targeting a metabolic vulnerability in a subset of low HIF1alpha/low MEIS1-expressing MLL-rearranged leukemia cells that present more glycolytic metabolic phenotype [ xref ]."
38704604
sparser
"Furthermore, another rare frequent translocation correlated with poor prognosis in pediatric T-ALL is t(10;11)(p13;q14), which creates CALM-AF10 fusion gene ( xref )."
32010613
sparser
"In concordance with our findings in the human cell line models, we found an increase in total protein expression and plasma membrane receptor expression in the murine CALM-AF10 leukemia cells relative to the Hoxa9-Meis1 translocated cells ( xref )."
35070954
sparser
"We next examined the potential of CXCR4 as a therapeutic target in CALM-AF10 -driven leukemia."
35070954
sparser
"We co-cultured the CALM-AF10 expressing U937 cell line with human mesenchymal stem cells (hMSCs) to model the interaction between the bone marrow microenvironment and leukemia cells."
35070954
sparser
"Western blot analysis revealed a decrease specifically in the phosphorylated ERK after AMD3465 treatment ( xref ), confirming an active CXCR4 signaling cascade in CALM-AF10 expressing leukemia cells."
35070954
sparser
"Human leukemia cells lines U937 ( CALM-AF10 +) or Kasumi-1 ( CALM-AF10 negative) were treated for 48 hours, and cell proliferation was quantified via BrdU assay."
35070954
sparser
"At least one mutation was identified in > 50% of T-cell lineage ALL, which included representatives of all major molecular subtypes of T-cell ALL (HOX11, HOX11L2, TAL1, LYL1, MLL-ENL or CALM-AF10)."
16083331
sparser
"CALM-AF10 leukemias typically show a poor response to therapy, have an increased propensity to relapse and have a worse overall prognosis."
35070954
sparser
"Interestingly, CALM-AF10 leukemias have a high prevalence of extramedullary disease, including bulky mediastinal disease, and a propensity for central nervous system relapse."
35070954
sparser
"We therefore examined the migratory properties of cells transformed by CALM-AF10 and found that MEFs transformed by CALM-AF10 exhibited enhanced cell migration in scratch assays, compared with controls."
35070954
sparser
"We then examined cell migration in CALM-AF10 + leukemia cells via transwell migration assays and discovered that CALM-AF10 + U937 cells show enhanced migration in transwell assays, compared with CALM-AF10 negative Kasumi-1 cells."
35070954
sparser
"4.2 Increased CXCR4 Expression Is Seen in CALM-AF10 Leukemia and Contributes to Cell Migration."
35070954
sparser
"The second most frequent subtype (20–25%) had HOXA-t , CALM-AF10 , and KMT2A -rearrangements ( KMT2A-R )."
33467425
sparser
"Based on our findings of increased CXCR4 expression on CALM-AF10 leukemic blasts, and the contribution of CXCR4 to CALM-AF10 + cell migration, we hypothesized that these cells would be particularly sensitive to CXCR4 inhibition as a chemosensitizer."
35070954
sparser
"We first established that CALM-AF10 expressing leukemia cells have an active CXCR4 signaling cascade by observing a reduction in phophoERK to ERK after CXCR4 inhibition."
35070954
sparser
"Acute leukemia with a PICALM–MLLT10 fusion gene (alias CALM–AF10 ) has been very rarely reported [1–3] ."
20875875
sparser
"The t(10;11)(p13;q21) rearrangement results in the production of a PICALM–MLLT10 fusion gene (alias CALM–AF10 ) [1] ."
20875875
sparser
"This approach revealed that one case each was positive for TLX1, TLX3, TRA-MYC, KMT2A-MLLT4 (MLL-AF6), PICALMMLLT10 (CALM-AF10), and TRB-HOXA; and one harbored a cryptic LMO2-activating deletion [30] detected by aCGH and confirmed by FISH (Table 1; Supplementary Table S2)."
28482719
sparser
"Similar CALM–AF10 + B-lymphoid progenitors were identified in several patients with CALM–AF10-associated AML, although these cells were not assessed for LSC activity by xenotransplantation."
17981087
sparser
"These observations suggest that a transformed progenitor with B-lymphoid characteristics can propagate CALM–AF10 + AML, emphasizing the potential LSC diversity that might be present in human AML."
17981087
sparser
"In addition, HOXA gene cluster dysregulation may occur in T-ALL cases with MLL, CALM-AF10, or SET-NUP214 fusions ( Soulier et al., 2005 ; Bergeron et al., 2006 ; Van Vlierberghe et al., 2008 )."
33578108
sparser
"Although both cell lines are driven by CALM-AF10 fusions, they exhibit differential sensitivity to ENL knockout, providing lineage- and oncogene-matched models of sensitive and resistant acute leukemia ( xref )."
41142648
sparser
"The CALM-AF10 fusion gene transforms hematopoietic progenitors through the functions mediated by the NES and the OM-LG domain which binds to DOT1L and AF9/ENL proteins."
40950097
sparser
"In this study, we demonstrate that the CCCTC‐binding factor (CTCF) plays a critical role in both the initiation and maintenance of CALM‐AF10‐induced AML (CALM‐AF10 AML)."
40875517
sparser
"In vivo, CTCF deficiency significantly extended the survival of CALM‐AF10 AML mice."
40875517
sparser
"However, DOT1L is functionally required for the malignant transformation of hematopoietic progenitors involving the oncogenic gene-fusion products MLL-AF10, CALM-AF10, MLL-AF4 and MLL-AF9 ( Okada et a[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
25578037
sparser
"Interestingly, in the CALM-AF10 chimaeric protein the clathrin-binding region of CALM is conserved and could sequester clathrin away from wild-type CALM [67] , thus impairing the formation of coated-p[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
15943966
sparser
"The PICALM::MLLT10 (also known as CALM::AF10 ) fusion transcript has first been discovered in the U-937 histiocytic lymphoma cell line [ xref , xref ]."
40983660
sparser
"Notably THP‐1 (MLL‐AF9), U937 (CALM‐AF10 fusion), EOL‐1 (MLL‐PTD mutation), and OCI‐AML3 (NPM1c+ mutation) exhibited a strong correlation with HOXA9 expression (Figure  xref ) and were therefore included for subsequent evaluation."
38716146
sparser
"CRM1 was found to recruit CALM-AF10 into the HOXA cluster, resulting in increased expression of the HOXA gene and eventual cell transformation."
35117001
sparser
"Thus, CALM-AF10 causes the occurrence of leukemia mainly by upregulating the expression of Hox homeobox genes, including HOXA5 , HOXA7 , HOXA9 and HOXA10 ( xref , xref , xref )."
35117001
sparser
"The incidence of CALM-AF10 in patients with T-ALL, including both adults and children, is reported to be greater than 10% ( xref )."
35117001
sparser
"In vitro analyses, although the cells expressing CALM‐AF10 (CALM‐AF10 AML cells) were able to form colonies in methylcellulose‐based semi‐solid media, Ctcf ‐deficient cells were incapable of forming colonies beyond the initial round (Figure  xref )."
40875517
sparser
"This review highlights several gene mutations with a high frequency or a strong influence associated with favorable or unfavorable aspects of prognosis— NOTCH1 , FBXW7 , PTEN , LOH6q, CASP8AP2 , c-MYC , IL-7 , CALM-AF10 , and CDKN2A/B —and indicates that the actual incidence of mutations in T-ALL/LBL is much higher than currently recognized."
35117001
sparser
"Gene expression profiling has identified several potential prognostic indicators of inherited T-LBL, such as NOTCH1 , F-box and WD repeat domain-containing 7 ( FBXW7 ), phosphatase and tensin homolog ( PTEN ), loss of heterozygosity at chromosome 6q (LOH6q), CASP8-associated protein 2 ( CASP8AP2 ), c-MYC , interleukin-7 ( IL-7 ), CALM-AF10 , and cyclin-dependent kinase inhibitor 2A/B ( CDKN2A/B )."
35117001
sparser
"This observation underscores the critical necessity of CTCF for the maintenance of the undifferentiated state in CALM‐AF10 AML cells."
40875517
sparser
"Furthermore, May Grunwald Giemsa staining indicated that loss of Ctcf induced a marked differentiation of CALM‐AF10 AML cells towards a macrophage‐like phenotype (Figure  xref )."
40875517
sparser
"In addition, NUP98 fusion genes, including the NHD13 fusion, commonly activate HOXA/B genes ( xref ), which are associated with stem cell self-renewal signatures, and are downstream targets of a wide spectrum of mutations associated with leukemia, including MLL fusions, CALM-AF10 fusion, monosomy 7, and NPM1 truncation mutations( xref )."
34321240
sparser
"In vivo, transformed cells expressing the CALM‐AF10 fusion gene were transplanted into irradiated recipient mice to establish a robust CALM‐AF10 AML model."
40875517
sparser
"CALM-AF10."
35117001
sparser
"CALM-AF10 was originally found in a patient with diffuse histiocytic lymphoma and later became the most common fusion protein in T-ALL ( xref , xref )."
35117001
sparser
"May Grunwald Giemsa staining showed that Tgm2 KD induced differentiation of CALM‐AF10 AML cells into macrophage‐like cells (Figure  xref ), a finding confirmed by FACS analysis, which revealed increased expression of macrophage markers CD68 and F4/80 (Figure  xref )."
40875517
sparser
"In the U937 leukemic cell line expressing the CALM‐AF10 fusion gene, Tgm2 KD also resulted in significantly reduced proliferation (Figure  xref )."
40875517
sparser
"These results highlight the essential role of TGM2 in maintaining the undifferentiated state and proliferative capacity of CALM‐AF10 AML cells."
40875517
sparser
"Given the striking phenotypic similarity between CTCF knockout and TGM2 knockdown in CALM‐AF10 AML cells (Figures  xref , xref ), we hypothesized that CTCF and TGM2 might co‐regulate a common set of genes."
40875517
sparser
"Because Ctcf KO and Tgm2 KD promoted the differentiation of CALM‐AF10 AML cells into macrophage‐like cells (Figures  xref and xref ), our GSEA analysis focused on gene sets associated with the stemness and differentiation of hematopoietic cells."
40875517
sparser
"MLL-AF10, MLL-ABI1 , and CALM-AF10 are fusion genes identified in leukemic patients with t (10;11)(p12;q23) ."
32273762