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

Jinyong Wang*, Guangyao Kong, Yangang Liu, Juan Du, Yuan I. Chang, Sin Ruow Tey, Xinmin Zhang, Erik A. Ranheim, Marc K. Saba-El-Leil, Sylvain Meloche, Alisa Damnernsawad, Jingfang Zhang, Jing Zhang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


Oncogenic NRAS mutations 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.

Original languageEnglish
Pages (from-to)5203-5207
Number of pages5
Issue number6
StatePublished - 27 Jun 2013


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