1. NrasG12D/+ promotes leukemogenesis by aberrantly regulating hematopoietic stem cell functions
- Author
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Juan Du, Jing Zhang, Sin Ruow Tey, Guangyao Kong, Jingfang Zhang, Alisa Damnernsawad, Marc K. Saba-El-Leil, Sylvain Meloche, Xinmin Zhang, Erik A. Ranheim, Yangang Liu, Jinyong Wang, and Yuan I. Chang
- Subjects
Neuroblastoma RAS viral oncogene homolog ,Myeloid ,Immunology ,MAP Kinase Kinase 1 ,Mice, Transgenic ,Biology ,Biochemistry ,GTP Phosphohydrolases ,Mice ,medicine ,Animals ,Humans ,Phosphorylation ,Progenitor cell ,Mitogen-Activated Protein Kinase 3 ,Myeloid Neoplasia ,Membrane Proteins ,Hematopoietic stem cell ,hemic and immune systems ,Leukemia, Myelomonocytic, Chronic ,Cell Biology ,Hematology ,Flow Cytometry ,Hematopoietic Stem Cells ,medicine.disease ,Leukemia ,Haematopoiesis ,medicine.anatomical_structure ,Mutation ,Cancer research ,Bone marrow ,Stem cell ,Signal Transduction - 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.
- Published
- 2013