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Molecular studies reveal MLL-MLLT10/AF10 and ARID5B-MLL gene fusions displaced in a case of infantile acute lymphoblastic leukemia with complex karyotype.

ABSTRACT: The present report describes a unique infantile acute lymphoblastic leukemia (ALL) case with cryptic mixed-lineage leukemia (MLL) rearrangements with 11q23 chromosomal translocation. MLL break-apart signals were identified by fluorescence in situ hybridization, and transcriptome sequencing revealed MLL-myeloid/lymphoid or mixed-lineage leukemia; translocated To, 10 (MLLT10)/AF10 fusion transcripts. Analysis also revealed a previously unreported MLLT10/AF10-homeobox protein Mohawk (MKX) transcript, where the 5' portion of MLLT10/AF10 at 10p12.31 was fused out-of-frame with the 3' portion of MKX at 10p12.1, which is closely located to MLLT10/AF10. Furthermore, the reciprocal 3'-MLL gene segment was fused in-frame to AT-rich interaction domain (ARID)5B at 10q21. Previously, common allelic variants in ARID5B, which are directly associated with hematopoietic differentiation and development, have been repeatedly and significantly associated with childhood ALL. The heterozygous genotype in ARID5B (RefSNP: rs10821936) increased the risk for leukemia with MLL-rearrangement. In particular, single nucleotide polymorphisms of ARID5B conferred increased risk for MLL-MLLT3/AF9. Based on these findings, the authors propose that while the presence of reciprocal MLL alleles has been detected in this patient, different pathological disease mechanisms may be at play due to individual recombination events.

SUBMITTER: Hiwatari M

PROVIDER: S-EPMC5530220 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Molecular studies reveal MLL-MLLT10/AF10 and ARID5B-MLL gene fusions displaced in a case of infantile acute lymphoblastic leukemia with complex karyotype.

Hiwatari Mitsuteru M Seki Masafumi M Akahoshi Shogo S Yoshida Kenichi K Miyano Satoru S Shiraishi Yuichi Y Tanaka Hiroko H Chiba Kenichi K Ogawa Seishi S Takita Junko J

Oncology letters 20170620 2

The present report describes a unique infantile acute lymphoblastic leukemia (ALL) case with cryptic mixed-lineage leukemia (MLL) rearrangements with 11q23 chromosomal translocation. MLL break-apart signals were identified by fluorescence in situ hybridization, and transcriptome sequencing revealed MLL-myeloid/lymphoid or mixed-lineage leukemia; translocated To, 10 (MLLT10)/AF10 fusion transcripts. Analysis also revealed a previously unreported MLLT10/<i ...[more]

PMID: 28781666

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Project description:Wnt signaling maintains the undifferentiated state of intestinal crypt progenitor cells by inducing the formation of nuclear TCF4/β-catenin complexes. In colorectal cancer, activating mutations in Wnt pathway components cause inappropriate activation of TCF4/β-catenin-driven transcription. Despite the passage of a decade after the discovery of TCF4 and β-catenin as the molecular effectors of the Wnt signal, few transcriptional activators essential and unique to the regulation of this transcription program have been found. Using proteomics, we identified the leukemia-associated Mllt10/Af10 and the methyltransferase Dot1l as Tcf4/β-catenin interactors in mouse small intestinal crypts. Mllt10/Af10-Dot1l, essential for transcription elongation, are recruited to Wnt target genes in a β-catenin-dependent manner, resulting in H3K79 methylation over their coding regions in vivo in proliferative crypts of mouse small intestine in colorectal cancer and Wnt-inducible HEK293T cells. Depletion of MLLT10/AF10 in colorectal cancer and Wnt-inducible HEK293T cells followed by expression array analysis identifies MLLT10/AF10 and DOT1L as essential activators to a large extent dedicated to Wnt target gene regulation. In contrast, previously published β-catenin coactivators p300 and BRG1 displayed a more pleiotropic target gene expression profile controlling Wnt and other pathways. tcf4, mllt10/af10, and dot1l are co-expressed in Wnt-driven tissues in zebrafish and essential for Wnt-reporter activity. Intestinal differentiation defects in apc-mutant zebrafish can be rescued by depletion of Mllt10 and Dot1l, establishing these genes as activators downstream of Apc in Wnt target gene activation in vivo. Morpholino-depletion of mllt10/af10-dot1l in zebrafish results in defects in intestinal homeostasis and a significant reduction in the in vivo expression of direct Wnt target genes and in the number of proliferative intestinal epithelial cells. We conclude that Mllt10/Af10-Dot1l are essential, largely dedicated activators of Wnt-dependent transcription, critical for maintenance of intestinal proliferation and homeostasis. The methyltransferase DOT1L may present an attractive candidate for drug targeting in colorectal cancer.

Dataset Information

Molecular studies reveal MLL-MLLT10/AF10 and ARID5B-MLL gene fusions displaced in a case of infantile acute lymphoblastic leukemia with complex karyotype.

Publications

Molecular studies reveal <i>MLL-MLLT10/AF10</i> and <i>ARID5B-MLL</i> gene fusions displaced in a case of infantile acute lymphoblastic leukemia with complex karyotype.

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