TAL1/SCL induces leukemia by inhibiting the transcriptional activity of E47/HEB

Cancer Cell. 2004 Jun;5(6):587-96. doi: 10.1016/j.ccr.2004.05.023.

Abstract

Activation of the basic-helix-loop-helix (bHLH) gene TAL1 (or SCL) is a frequent gain-of-function mutation in T cell acute lymphoblastic leukemia (T-ALL). To provide genetic evidence that tal1/scl induces leukemia by interfering with E47 and HEB, we expressed tal1/scl in an E2A or HEB heterozygous background. These mice exhibit disease acceleration and perturbed thymocyte development due to repression of E47/HEB target genes. In tal1/scl thymocytes, we find the corepressor mSin3A bound to the CD4 enhancer, whereas an E47/HEB/p300 complex is detected in wild-type thymocytes. Furthermore, tal1/scl tumors are sensitive to pharmacologic inhibition of HDAC and undergo apoptosis. These data demonstrate that tal1/scl induces leukemia by repressing E47/HEB and suggest that HDAC inhibitors may prove efficacious in T-ALL patients who express TAL1/SCL.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Basic Helix-Loop-Helix Transcription Factors
  • Blotting, Northern
  • Blotting, Western
  • CD4 Antigens / biosynthesis
  • CD4 Antigens / metabolism
  • CD5 Antigens / biosynthesis
  • Chromatin / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Flow Cytometry
  • Immunophenotyping
  • Intracellular Signaling Peptides and Proteins
  • Loss of Heterozygosity
  • Mice
  • Mice, Transgenic
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Oncogene Proteins, Fusion / metabolism
  • Oncogene Proteins, Fusion / physiology*
  • Precipitin Tests
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • TCF Transcription Factors
  • Thymus Gland / cytology
  • Thymus Gland / metabolism
  • Time Factors
  • Transcription Factor 7-Like 1 Protein
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Transcription, Genetic*

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • CD4 Antigens
  • CD5 Antigens
  • Chromatin
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Oncogene Proteins, Fusion
  • STIL protein, human
  • TCF Transcription Factors
  • TCF7L1 protein, human
  • Tcf12 protein, mouse
  • Tcf7l1 protein, mouse
  • Transcription Factor 7-Like 1 Protein
  • Transcription Factors
  • TCF12 protein, human