期刊
PLOS BIOLOGY
卷 7, 期 3, 页码 537-548出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pbio.1000059
关键词
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资金
- National Institutes of Health [R37 CA72614, U01 CA84221, K08 CA103868]
- Leukemia and Lymphoma Society [LLS 7019-04]
- V Foundation for Cancer Research
- Concern Foundation
- Connor Foundation
- Campini Foundation
- Fonds de la recherche en sante du Quebec
- St. Baldrick's Foundation
- American Society of Hematology
- Howard Hughes Medical Institute
How oncogenes modulate the self-renewal properties of cancer-initiating cells is incompletely understood. Activating KRAS and NRAS mutations are among the most common oncogenic lesions detected in human cancer, and occur in myeloproliferative disorders (MPDs) and leukemias. We investigated the effects of expressing oncogenic Kras(G12D) from its endogenous locus on the proliferation and tumor-initiating properties of murine hematopoietic stem and progenitor cells. MPD could be initiated by Kras(G12D) expression in a highly restricted population enriched for hematopoietic stem cells (HSCs), but not in common myeloid progenitors. KrasG(12D) HSCs demonstrated a marked in vivo competitive advantage over wild-type cells. Kras(G12D) expression also increased the fraction of proliferating HSCs and reduced the overall size of this compartment. Transplanted Kras(G12D) HSCs efficiently initiated acute T-lineage leukemia/lymphoma, which was associated with secondary Notch1 mutations in thymocytes. We conclude that MPD-initiating activity is restricted to the HSC compartment in Kras(G12D) mice, and that distinct self-renewing populations with cooperating mutations emerge during cancer progression.
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