Open AccessOncogenic Kras Initiates Leukemia in Hematopoietic Stem Cells
Author(s) -
Amit J. Sabnis,
Laurene S. Cheung,
Monique Dail,
Hio Chung Kang,
Marianne Santaguida,
Michelle L. Hermiston,
Emmanuelle Passegué,
Kevin Shan,
Benjamin S. Braun
Publication year - 2009
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.1000059
Subject(s) - kras , biology , haematopoiesis , cancer research , stem cell , leukemia , progenitor cell , cancer stem cell , myeloid leukemia , myeloid , population , immunology , neuroblastoma ras viral oncogene homolog , carcinogenesis , cancer , genetics , medicine , colorectal cancer , environmental health
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. Kras G12D 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.