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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis
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Basic Helix-Loop-Helix Transcription Factors
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Blotting, Northern
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Blotting, Western
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CD4 Antigens / biosynthesis
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CD4 Antigens / metabolism
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CD5 Antigens / biosynthesis
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Chromatin / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Flow Cytometry
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Immunophenotyping
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Intracellular Signaling Peptides and Proteins
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Loss of Heterozygosity
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Mice
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Mice, Transgenic
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Mutation
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Oligonucleotide Array Sequence Analysis
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Oncogene Proteins, Fusion / metabolism
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Oncogene Proteins, Fusion / physiology*
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Precipitin Tests
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
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TCF Transcription Factors
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Thymus Gland / cytology
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Thymus Gland / metabolism
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Time Factors
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Transcription Factor 7-Like 1 Protein
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Transcription, Genetic*
Substances
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Basic Helix-Loop-Helix Transcription Factors
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CD4 Antigens
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CD5 Antigens
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Chromatin
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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Oncogene Proteins, Fusion
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STIL protein, human
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TCF Transcription Factors
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TCF7L1 protein, human
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Tcf12 protein, mouse
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Tcf7l1 protein, mouse
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Transcription Factor 7-Like 1 Protein
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Transcription Factors
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TCF12 protein, human