title: Nras(G12D/+) promotes leukemogenesis by aberrantly regulating hematopoietic stem cell functions.
abstract: 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.
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA. wang_jinyong@gibh.ac.cn
authors.forename: Jinyong
authors.initials: J
authors.lastname: Wang
authors.forename: Guangyao
authors.initials: G
authors.lastname: Kong
authors.forename: Yangang
authors.initials: Y
authors.lastname: Liu
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Yuan-I
authors.initials: YI
authors.lastname: Chang
authors.forename: Sin Ruow
authors.initials: SR
authors.lastname: Tey
authors.forename: Xinmin
authors.initials: X
authors.lastname: Zhang
authors.forename: Erik A
authors.initials: EA
authors.lastname: Ranheim
authors.forename: Marc K
authors.initials: MK
authors.lastname: Saba-El-Leil
authors.forename: Sylvain
authors.initials: S
authors.lastname: Meloche
authors.forename: Alisa
authors.initials: A
authors.lastname: Damnernsawad
authors.forename: Jingfang
authors.initials: J
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D005434:Flow Cytometry; D020558:GTP Phosphohydrolases / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D015398:Signal Transduction
chemical_list: D008565:Membrane Proteins; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human