Nras^G12D/+ promotes leukemogenesis by aberrantly regulating hematopoietic stem cell functions

Oncogenic NRAS mutations are frequently identified in human myeloid leukemias. In mice, expression of endogenous oncogenic Nras (Nras^G12D/+) 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 Nras^G12D/+ 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 Nras^G12D/+ signaling promotes leukemogenesis. Here, we show that hematopoietic stem cells (HSCs) expressing Nras^G12D/+ serve as MPN-initiating cells. They undergo moderate hyperproliferation with increased self-renewal. The aberrant Nras^G12D/+ 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 Nras^G12D/+ HSCs and prevents the expansion of Nras^G12D/+ HSCs and myeloid progenitors. Our data delineate critical mechanisms of oncogenic Nras signaling in HSC function and leukemogenesis.