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

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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 1 2014

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All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

Cite this

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. (2014). Aberrant TAL1 activation is mediated by an interchromosomal interaction in human T-cell acute lymphoblastic leukemia. Leukemia, 28(2), 349-361. https://doi.org/10.1038/leu.2013.158