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

Authors: Guryanova, O. A.; Lieu, Y. K.; Garrett-Bakelman, F. E.; Spitzer, B.; Glass, J. L.; Shank, K.; Martinez, A. B. V.; Rivera, S. A.; Durham, B. H.; Rapaport, F.; Keller, M. D.; Pandey, S.; Bastian, L.; Tovbin, D.; Weinstein, A. R.; Teruya-Feldstein, J.; Abdel-Wahab, O.; Santini, V.; Mason, C. E.; Melnick, A. M.; Mukherjee, S.; Levine, R. L.
Article Title: Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells
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.
Keywords: chronic myelomonocytic leukemia; erythropoiesis; self-renewal; myelodysplastic syndromes; differentiation; transformation; mutations; acute myeloid-leukemia; fetal; leads
Journal Title: Leukemia
Volume: 30
Issue: 5
ISSN: 0887-6924
Publisher: Nature Publishing Group  
Date Published: 2016-05-01
Start Page: 1133
End Page: 1142
Language: English
ACCESSION: WOS:000375691800015
DOI: 10.1038/leu.2015.358
PMCID: PMC4856586
PUBMED: 26710888
Notes: Article -- Source: Wos
Citation Impact
MSK Authors
  1. Julie T Feldstein
    290 Feldstein
  2. Ross Levine
    540 Levine
  3. Barbara Spitzer
    35 Spitzer
  4. Suveg Pandey
    11 Pandey
  5. Kaitlyn Ruth Shank
    20 Shank
  6. Matthew D Keller
    25 Keller
  7. Jacob Lowell Glass
    21 Glass
  8. Benjamin Heath Durham
    73 Durham
  9. Daniel   Tovbin
    3 Tovbin