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Leukemogenesis

Loss of Dnmt3a and endogenous KrasG12D/+ cooperate to regulate hematopoietic stem and progenitor cell functions in leukemogenesis

Leukemia volume 29, pages 1847–1856 (2015)Cite this article

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Abstract

Oncogenic NRAS and KRAS mutations are prevalent in human juvenile and chronic myelomonocytic leukemia (JMML/CMML). However, additional genetic mutations cooperating with oncogenic RAS in JMML/ CMML progression and/or their transformation to acute myeloid leukemia (AML) remain largely unknown. Here we tested the potential genetic interaction of DNMT3A mutations and oncogenic RAS mutations in leukemogenesis. We found that Dnmt3a−/− induces multiple hematopoietic phenotypes after a prolonged latency, including T-cell expansion in the peripheral blood, stress erythropoiesis in the spleen and myeloid malignancies in the liver. Dnmt3a−/− significantly promoted JMML/CMML progression and shortened the survival of KrasG12D/+ mice in a cell-autonomous manner. Similarly, downregulating Dnmt3a also promoted myeloid malignancies in NrasG12D/+ mice. Further studies show that Dnmt3a deficiency rescues KrasG12D/+-mediated depletion of hematopoietic stem cells and increases self-renewal of KrasG12D/+ myeloid progenitors (MPs). Moreover, ~33% of animals developed an AML-like disease, which is driven by KrasG12D/+; Dnmt3a−/− MPs. Consistent with our result, COSMIC database mining demonstrates that the combination of oncogenic RAS and DNMT3A mutations exclusively occurred in patients with JMML, CMML or AML. Our results suggest that DNMT3A mutations and oncogenic RAS cooperate to regulate hematopoietic stem and progenitor cells and promote myeloid malignancies.

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Acknowledgements

We are grateful to Dr Qiang Chang for providing the Dnmt3a conditional knockout mice. We thank the University of Wisconsin Carbone Comprehensive Cancer Center (UWCCC) for use of its Shared Services to complete this research. This work was supported by R01 grants R01CA152108 and R01HL113066, and a Scholar Award from the Leukemia & Lymphoma Society to JZ. Y-IC was supported by the Ministry of Science and Technology (MOST 103-2320-B-010-047) and a grant from Ministry of Education, Aim for the Top University Plan. This work was also supported in part by NIH/NCI P30 CA014520–UW Comprehensive Cancer Center Support.

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Authors and Affiliations

  1. McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA

    Y-I Chang, X You, G Kong, J Wang, J Du, Y Liu, Y Zhou, M-J Ryu & J Zhang

  2. Institute of Physiology, National Yang-Ming University, Taipei City, Taiwan

    Y-I Chang

  3. Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin Carbone Cancer Center, Madison, WI, USA

    E A Ranheim

  4. Department of Medical Science, School of Medicine, Yonsei University, Seoul, Korea

    M-J Ryu

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  1. Y-I Chang
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Chang, YI., You, X., Kong, G. et al. Loss of Dnmt3a and endogenous KrasG12D/+ cooperate to regulate hematopoietic stem and progenitor cell functions in leukemogenesis. Leukemia 29, 1847–1856 (2015). https://doi.org/10.1038/leu.2015.85

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