Oncogenic Kras Initiates Leukemia In Hematopoietic Stem Cells

Main Category: Lymphoma / Leukemia / Myeloma
Also Included In: Stem Cell Research;  Blood / Hematology;  Cancer / Oncology
Article Date: 17 Mar 2009 - 5:00 PDT


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. The authors investigated the effects of expressing oncogenic KrasG12D from its endogenous locus on the proliferation and tumor-initiating properties of murine hematopoietic stem and progenitor cells. MPD could be initiated by KrasG12D expression in a highly restricted population enriched for hematopoietic stem cells (HSCs), but not in common myeloid progenitors. KrasG12D HSCs demonstrated a marked in vivo competitive advantage over wild-type cells.

KrasG12D expression also increased the fraction of proliferating HSCs and reduced the overall size of this compartment. Transplanted KrasG12D HSCs efficiently initiated acute T-lineage leukemia/lymphoma, which was associated with secondary Notch1 mutations in thymocytes. The authors conclude that MPDinitiating activity is restricted to the HSC compartment in KrasG12D mice, and that distinct self-renewing populations with cooperating mutations emerge during cancer progression.

Citation:
"Oncogenic Kras initiates leukemia in hematopoietic stem cells."
Sabnis AJ, Cheung LS, Dail M, Kang HC, Santaguida M, et al. (2009)
PLoS Biol 7(3): e1000059. doi:10.1371/journal.pbio.1000059
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