| First Author | Wang J | Year | 2013 |
| Journal | Blood | Volume | 121 |
| Issue | 26 | Pages | 5203-7 |
| PubMed ID | 23687087 | Mgi Jnum | J:201009 |
| Mgi Id | MGI:5510634 | Doi | 10.1182/blood-2012-12-475863 |
| Citation | Wang J, et al. (2013) Nras(G12D/+) promotes leukemogenesis by aberrantly regulating hematopoietic stem cell functions. Blood 121(26):5203-7 |
| abstractText | 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. |
