TAL1/SCL induces leukemia by inhibiting the transcriptional activity of E47/HEB
Copyright policy )TAL1/SCL induces leukemia by inhibiting the transcriptional activity of E47/HEB
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.
- University of California, San Diego United States
- University of Massachusetts Medical School United States
- University of California, San Diego United States
- University of California, San Francisco United States
Cancer Research, Oncogene Proteins, Fusion, Blotting, Western, 610, Loss of Heterozygosity, Apoptosis, Mice, Transgenic, CD5 Antigens, Immunophenotyping, Mice, 616, Basic Helix-Loop-Helix Transcription Factors, Animals, Oligonucleotide Array Sequence Analysis, Intracellular Signaling Peptides and Proteins, Cell Biology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Blotting, Northern, Flow Cytometry, Precipitin Tests, Chromatin, DNA-Binding Proteins, Oncology, CD4 Antigens, Mutation
Cancer Research, Oncogene Proteins, Fusion, Blotting, Western, 610, Loss of Heterozygosity, Apoptosis, Mice, Transgenic, CD5 Antigens, Immunophenotyping, Mice, 616, Basic Helix-Loop-Helix Transcription Factors, Animals, Oligonucleotide Array Sequence Analysis, Intracellular Signaling Peptides and Proteins, Cell Biology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Blotting, Northern, Flow Cytometry, Precipitin Tests, Chromatin, DNA-Binding Proteins, Oncology, CD4 Antigens, Mutation
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