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.
O'Neil
Jennifer
J
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Shank
Jennifer
J
Cusson
Nicole
N
Murre
Cornelis
C
Kelliher
Michelle
M
D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins; D015152:Blotting, Northern; D015153:Blotting, Western; D015704:CD4 Antigens / Q000096:biosynthesis / Q000378:metabolism; D018956:CD5 Antigens / Q000096:biosynthesis; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005434:Flow Cytometry; D016130:Immunophenotyping; D047908:Intracellular Signaling Peptides and Proteins; D019656:Loss of Heterozygosity; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000378:metabolism / Q000502:physiology*; D011233:Precipitin Tests; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism*; D051820:TCF Transcription Factors; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D015704:CD4 Antigens; D018956:CD5 Antigens; D002843:Chromatin; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015514:Oncogene Proteins, Fusion; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; D014157:Transcription Factors; C071236:STIL protein, human; C544912:TCF7L1 protein, human; C489532:Tcf12 protein, mouse; C544913:Tcf7l1 protein, mouse; C073366:TCF12 protein, human