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Leukemia. 2017 Nov;31(11):2479-2490. doi: 10.1038/leu.2017.89. Epub 2017 Mar 21.

Dnmt3a regulates T-cell development and suppresses T-ALL transformation.

Author information

1
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA.
2
Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
3
College of Arts and Science, Washington University in St Louis, One Brookings Drive, St Louis, MO, USA.
4
Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, MO, USA.
5
Department of Pathology, University of Michigan Medical School, 1500 E Medical Center Dr, Ann Arbor, MI, USA.
6
Center of Regenerative Medicine, Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, USA.
7
Developmental, Regenerative and Stem Cell Biology Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St Louis, MO, USA.

Abstract

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.

PMID:
28321121
PMCID:
PMC5636646
DOI:
10.1038/leu.2017.89
[Indexed for MEDLINE]
Free PMC Article

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