Dnmt3a regulates myeloproliferation and liver-specific homing and expansion of hematopoietic stem and progenitor cells (RNA-Seq)

DNMT3A mutations are observed in myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). Here we investigated the impact of conditional hematopoietic Dnmt3a loss on disease phenotype in primary mice. Dnmt3a ablation led to a lethal, fully penetrant myeloproliferative neoplasm with myelodysplasia (MDS/MPN) characterized by marked, progressive hepatomegaly that was transplantable. We detected expanded stem/progenitor populations in the liver of Dnmt3a-ablated mice. Homing studies showed that Dnmt3a-deleted bone marrow cells preferentially migrated to the liver. Hence, in addition to the established role of Dnmt3a in regulating self-renewal, Dnmt3a regulates tissue tropism and limits myeloid progenitor expansion in vivo. Overall design: Dnmt3af/f mice (Nguyen et al) were crossed into hematopoietic-specific inducible Mx1-Cre deletor line; we examined transcriptomes from FACS-sorted LSK and GMP populations from Dnmt3af/f Mx1-Cre+ (KO) and Dnmt3af/f Mx1-Cre- (CTRL) animals at 12 months of age

10

Guryanova OA, Lieu YK, Garrett-Bakelman FE, Spitzer B, Glass JL, Shank K, Martinez AB, Rivera SA, Durham BH, Rapaport F, Keller MD, Pandey S, Bastian L, Tovbin D, Weinstein AR, Teruya-Feldstein J, Abdel-Wahab O, Santini V, Mason CE, Melnick AM, Mukherjee S, Levine RL