NrasG12D/+promotes leukemogenesis by aberrantly regulating hematopoietic stem cell functions

Oncogenic NRASmutations are frequently identified in human myeloid leukemias. In mice, expression of endogenous oncogenic Nras (NrasG12D/+) in hematopoietic cells leads to expansion of myeloid progenitors, increased long-term reconstitution of bone marrow cells, and a chronic myeloproliferative neoplasm (MPN). However, acute expression of NrasG12D/+in a pure C57BL/6 background does not induce hyperactivated granulocyte macrophage colony-stimulating factor signaling or increased proliferation in myeloid progenitors. It is thus unclear how NrasG12D/+signaling promotes leukemogenesis. Here, we show that hematopoietic stem cells (HSCs) expressing NrasG12D/+serve as MPN-initiating cells. They undergo moderate hyperproliferation with increased self-renewal. The aberrant NrasG12D/+HSC function is associated with hyperactivation of ERK1/2 in HSCs. Conversely, downregulation of MEK/ERK by pharmacologic and genetic approaches attenuates the cycling of NrasG12D/+HSCs and prevents the expansion of NrasG12D/+HSCs and myeloid progenitors. Our data delineate critical mechanisms of oncogenic Nras signaling in HSC function and leukemogenesis.