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

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


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.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • CCCTC-Binding Factor
  • Cell Line, Tumor
  • Chromatin / metabolism
  • Chromosomes, Human, Pair 16
  • Enhancer Elements, Genetic
  • Epistasis, Genetic*
  • Erythroid Precursor Cells / metabolism
  • Gene Expression Regulation, Leukemic
  • Gene Order
  • Genetic Loci
  • Hematopoiesis / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histones / metabolism
  • Humans
  • Organ Specificity / genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-maf / metabolism
  • Regulatory Sequences, Nucleic Acid
  • Repressor Proteins / metabolism
  • T-Cell Acute Lymphocytic Leukemia Protein 1
  • Transcriptional Activation*
  • p300-CBP Transcription Factors / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • CCCTC-Binding Factor
  • CTCF protein, human
  • Chromatin
  • Histones
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-maf
  • Repressor Proteins
  • T-Cell Acute Lymphocytic Leukemia Protein 1
  • TAL1 protein, human
  • Histone-Lysine N-Methyltransferase
  • Setd1A protein, human
  • p300-CBP Transcription Factors