Publication — IRIC

NrasG12D/+ 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.

Date de publication
27 juin 2013
Chercheurs
Wang J, Kong G, Liu Y, Du J, Chang YI, Tey SR, Zhang X, Ranheim EA, Saba-El-Leil MK, Meloche S, Damnernsawad A, Zhang J, Zhang J
Référence PubMed
Blood 2013;121(26):5203-7
ID PubMed
23687087
Affiliation
McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI;