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

B. Patel, Y. Kang, K. Cui, M. Litt, M. S.J. Riberio, C. Deng, T. Salz, S. Casada, X. Fu, Y. Qiu, K. Zhao, S. Huang

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)349-361
Number of pages13
JournalLeukemia
Volume28
Issue number2
DOIs
StatePublished - Feb 2014

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

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