Journal
LEUKEMIA
Volume 30, Issue 5, Pages 1133-1142Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2015.358
Keywords
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Funding
- NCI K99 grant [CA178191]
- Lauri Strauss Leukemia Foundation discovery grant
- NCI [K08 CA169055]
- ASH-AMFDP [20121]
- Robert Wood Johnson Foundation
- Gabrielle's Angel Fund grant
- Samuel Waxman Cancer Research Center
- Sackler Center for Biomedical and Physical Sciences
- Bert L and N Kuggie Vallee Foundation
- Irma T Hirschl and Monique Weill-Caulier Charitable Trusts
- WorldQuant Foundation
- STARR Consortium [I7-A765, I9-A9-071]
- [CA172636]
- [P30 CA008748]
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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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