title: Oncogenic NRAS hyper-activates multiple pathways in human cord blood stem/progenitor cells and promotes myelomonocytic proliferation in vivo.
abstract: Oncogenic NRAS mutations are prevalent in human myeloid leukemia, especially in chronic myelomonocytic leukemia (CMML). NrasG12D mutation at its endogenous locus in murine hematopoietic stem cells (HSCs) leads to CMML and acute T-cell lymphoblastic lymphoma/leukemia in a dose-dependent manner. Hyper-activated MAPK and STAT5 pathways by oncogenic Nras contribute to the leukemogenesis in vivo. However, it is unclear whether these conclusions remain true in a more human relevant model. Here, we evaluated the effects of NRASG12D on human hematopoiesis and leukemogenesis in vitro and in vivo by ectopically expressing NRASG12D in human cord blood stem/progenitor cells (hSPCs). NRASG12D expressing hSPCs preferentially differentiated into myelomonocytic lineage cells, demonstrated by forming more colony forming unit-macrophages than control hSPCs in cultures. Transplantation of NRASG12D expressing hSPCs initiated myeloproliferative neoplasm in immune deficiency mice. All the recipient mice died of myeloid tumor burdens in spleens and bone marrows and none developed lymphoid leukemia. Phospho-flow analysis of CD34(+) CD38(-) hSPCs confirmed that NRASG12D hyper-activated MAPK, AKT and STAT5 pathways. Our study provides the strong evidence that NRASG12D mutation mainly targets monocytic lineage cells and leads to myelomonocytic proliferation in vivo in a highly human relevant context.
authors.affiliation: School of Life Sciences, University of Science and Technology of China Anhui, China ; Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou, China.
authors.forename: Tongjie
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Hematology, The Third Affiliated Hospital of Sun Yat-sen University Guangzhou, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.affiliation: School of Life Sciences, University of Science and Technology of China Anhui, China ; Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou, China.
authors.forename: Chengxiang
authors.initials: C
authors.lastname: Xia
authors.affiliation: Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Yang
authors.affiliation: Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Geng
authors.affiliation: Laboratory Animal Center, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences China.
authors.forename: Jizhen
authors.initials: J
authors.lastname: Cai
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison Madison, WI 53706, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Hematology, The Third Affiliated Hospital of Sun Yat-sen University Guangzhou, China.
authors.forename: Xiangzhong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: School of Life Sciences, University of Science and Technology of China Anhui, China ; Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine Guangzhou, China.
authors.forename: Jinyong
authors.initials: J
authors.lastname: Wang
keywords: NRAS; hematopoietic stem/progenitor cells; immune deficiency mice; myelomonocytic proliferation