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

作者：Patel B; Kang Y; Cui K; Litt M; Riberio M S J; Deng C; Salz T; Casada S; Fu X; Qiu Y; Zhao K; Huang S^*

来源：Leukemia, 2014, 28(2): 349-361.

DOI：10.1038/leu.2013.158

• TAL1/SCL oncogene
• chromatin loops
• CTCF insulator
• T-cell leukemia
• epigenetic regulation

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-Mafmediated 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.

• 出版日期2014-2
• 单位吉林大学