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Leukemia. 2014 Feb;28(2):349-61. doi: 10.1038/leu.2013.158. Epub 2013 May 23.

Aberrant TAL1 activation is mediated by an interchromosomal interaction in human T-cell acute lymphoblastic leukemia.

Author information

1
Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA.
2
1] Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA [2] College of Life Science, Jilin University, Changchun, China.
3
Center for System Biology, NHLBI, National Institute of Health, Bethesda, MD, USA.
4
Medical Education Center, Ball State University, Muncie, IN, USA.
5
College of Life Science, Jilin University, Changchun, China.
6
1] Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL, USA [2] Shands Cancer Center, College of Medicine, University of Florida, Gainesville, FL, USA.
7
1] Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA [2] Shands Cancer Center, College of Medicine, University of Florida, Gainesville, FL, USA.

Abstract

Long-range chromatin interactions control metazoan gene transcription. However, the involvement of intra- and interchromosomal interactions in development and oncogenesis remains unclear. TAL1/SCL is a critical transcription factor required for the development of all hematopoietic lineages; yet, aberrant TAL1 transcription often occurs in T-cell acute lymphoblastic leukemia (T-ALL). Here, we report that oncogenic TAL1 expression is regulated by different intra- and interchromosomal loops in normal hematopoietic and leukemic cells, respectively. These intra- and interchromosomal loops alter the cell-type-specific enhancers that interact with the TAL1 promoter. We show that human SET1 (hSET1)-mediated H3K4 methylations promote a long-range chromatin loop, which brings the +51 enhancer in close proximity to TAL1 promoter 1 in erythroid cells. The CCCTC-binding factor (CTCF) facilitates this long-range enhancer/promoter interaction of the TAL1 locus in erythroid cells while blocking the same enhancer/promoter interaction of the TAL1 locus in human T-cell leukemia. In human T-ALL, a T-cell-specific transcription factor c-Maf-mediated interchromosomal interaction brings the TAL1 promoter into close proximity with a T-cell-specific regulatory element located on chromosome 16, activating aberrant TAL1 oncogene expression. Thus, our study reveals a novel molecular mechanism involving changes in three-dimensional chromatin interactions that activate the TAL1 oncogene in human T-cell leukemia.

PMID:
23698277
DOI:
10.1038/leu.2013.158
[Indexed for MEDLINE]

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