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Stem cell transplantation

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

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.

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Acknowledgements

We thank the Alvin J Siteman Cancer Center at Washington University School of Medicine for the use of the Siteman Flow Cytometry Core, which provided cell sorting and analysis. The Siteman Cancer Center is supported in part by NCI Cancer Center Support Grant CA91842. We thank the Genome Technology Access Center Washington University School of Medicine for genomic analysis. The Center is partially supported by NCI Cancer Center Support Grant CA91842 and by ICTS/CTSA Grant UL1TR000448 NIH, and NIH Roadmap for Medical Research. Research reported in this publication was supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR000448 NIH. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. This work was supported by grants (to GAC) from Alex’s Lemonade Stand Foundation, the Children’s Discovery Institute (MC-II-2013-286), the American Society of Hematology, and the Sidney Kimmel Foundation. WCW was supported by NIH T32HL008088. HC was supported by an American Society of Hematology scholar award. JN was supported in part by an Alex’s Lemonade Stand Foundation POST award. CM was supported in part by NIH T32HL008088, and NIH DK111058-01. ELO was supported by NIH 5T32CA113275-10.

Author contributions

Designed and performed experiments: ACK, AK, WCW, HC, JN, CM, EE, AM, GAC. Analyzed data: ELO, MCV, ALY, TED, MEF, BZ, GAC. Supervised the study and wrote the paper: GAC.

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Correspondence to G A Challen.

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Kramer, A., Kothari, A., Wilson, W. et al. Dnmt3a regulates T-cell development and suppresses T-ALL transformation. Leukemia 31, 2479–2490 (2017). https://doi.org/10.1038/leu.2017.89

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