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Stem cell biology

Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells

Leukemia volume 30, pages 1133–1142 (2016)Cite this article

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Abstract

DNA methyltransferase 3A (DNMT3A) mutations are observed in myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Transplantation studies have elucidated an important role for Dnmt3a in stem cell self-renewal and in myeloid differentiation. Here, we investigated the impact of conditional hematopoietic Dnmt3a loss on disease phenotype in primary mice. Mx1-Cre-mediated Dnmt3a ablation led to the development of a lethal, fully penetrant MPN with myelodysplasia (MDS/MPN) characterized by peripheral cytopenias and by marked, progressive hepatomegaly. We detected expanded stem/progenitor populations in the liver of Dnmt3a-ablated mice. The MDS/MPN induced by Dnmt3a ablation was transplantable, including the marked hepatomegaly. Homing studies showed that Dnmt3a-deleted bone marrow cells preferentially migrated to the liver. Gene expression and DNA methylation analyses of progenitor cell populations identified differential regulation of hematopoietic regulatory pathways, including fetal liver hematopoiesis transcriptional programs. These data demonstrate that Dnmt3a ablation in the hematopoietic system leads to myeloid transformation in vivo, with cell-autonomous aberrant tissue tropism and marked extramedullary hematopoiesis (EMH) with liver involvement. Hence, in addition to the established role of Dnmt3a in regulating self-renewal, Dnmt3a regulates tissue tropism and limits myeloid progenitor expansion in vivo.

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Acknowledgements

This work was supported by NCI K99 grant CA178191 and by Lauri Strauss Leukemia Foundation discovery grant to OAG, by NCI K08 CA169055 and ASH-AMFDP (20121) under the partnership with The Robert Wood Johnson Foundation to FGB, by a Gabrielle’s Angel Fund grant to RLL and AMM, by grant CA172636 to RLL and AMM and by the Samuel Waxman Cancer Research Center. AMM is a Burroughs Wellcome Clinical Translational Scholar, and is supported by the Sackler Center for Biomedical and Physical Sciences. RLL is an LLS Scholar. CEM is supported by the Bert L and N Kuggie Vallee Foundation, the Irma T Hirschl and Monique Weill-Caulier Charitable Trusts, the WorldQuant Foundation, and the STARR Consortium (I7-A765, I9-A9-071). MSKCC cores are supported by grant P30 CA008748. We thank Caroline Sheridan, Tak Lee, Jorge Gandara and the WCMC Epigenomics and ABC Cores for preparation and sequencing of next-generation sequencing assays and data services.

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Authors and Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    O A Guryanova, B Spitzer, K Shank, B H Durham, F Rapaport, M D Keller, S Pandey, L Bastian, D Tovbin, A R Weinstein, J Teruya-Feldstein, O Abdel-Wahab & R L Levine

  2. Department of Medicine, Irving Cancer Research Center, Columbia University, New York, NY, USA

    Y K Lieu, S A Rivera & S Mukherjee

  3. Department of Medicine, Weill Cornell Medical College, New York, NY, USA

    F E Garrett-Bakelman, J L Glass & A M Melnick

  4. Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    J L Glass, O Abdel-Wahab & R L Levine

  5. Hematology Unit, University of Florence, Florence, Italy

    A B V Martinez & V Santini

  6. Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, USA

    C E Mason

  7. Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    R L Levine

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  1. O A Guryanova
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Correspondence to S Mukherjee or R L Levine.

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Guryanova, O., Lieu, Y., Garrett-Bakelman, F. et al. Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells. Leukemia 30, 1133–1142 (2016). https://doi.org/10.1038/leu.2015.358

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