Dnmt3a regulates T-cell development and suppresses T-ALL transformation.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors, and comprises ~15% and 25% of pediatric and adult ALL cases, respectively. It is well-established that activating NOTCH1 mutations are the major genetic lesions driving T-ALL in most patients, but efforts to develop targeted therapies against this pathway have produced limited success in decreasing leukemic burden and come with significant clinical side effects. A finer detailed understanding of the genetic and molecular mechanisms underlying T-ALL is required identify patients at increased risk for treatment failure and the development of precision medicine strategies. Generation of genetic models that more accurately reflect the normal developmental history of T-ALL are necessary to identify new avenues for treatment. The DNA methyltransferase enzyme DNMT3A is also recurrently mutated in T-ALL patients, and we show here that inactivation of Dnmt3a combined with Notch1 gain-of-function leads to an aggressive T-ALL in mouse models. Moreover, conditional inactivation of Dnmt3a in mouse hematopoietic cells leads to an accumulation of immature progenitors in the thymus, which are less apoptotic. These data demonstrate that Dnmt3a is required for normal T-cell development, and acts as a T-ALL tumor suppressor.
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA.
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Kramer
Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
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Kothari
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA.
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Wilson
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA.
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Celik
College of Arts and Science, Washington University in St Louis, One Brookings Drive, St Louis, MO, USA.
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Nikitas
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA.
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Mallaney
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA.
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Ostrander
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA.
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Eultgen
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA.
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Martens
Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, MO, USA.
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Valentine
Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, MO, USA.
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Young
Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.|Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, MO, USA.
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Druley
Department of Pathology, University of Michigan Medical School, 1500 E Medical Center Dr, Ann Arbor, MI, USA.
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Figueroa
Center of Regenerative Medicine, Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, USA.
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Zhang
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA.|Developmental, Regenerative and Stem Cell Biology Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St Louis, MO, USA.
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Challen
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000502:physiology*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D013601:T-Lymphocytes / Q000166:cytology*
C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A