期刊
BLOOD
卷 109, 期 9, 页码 3945-3952出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2006-09-047530
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资金
- NCI NIH HHS [K08 CA103868, K08 CA 103868, R01 CA 72614, R01 CA072614] Funding Source: Medline
- NHLBI NIH HHS [N01HV28183, N01 HV 28183] Funding Source: Medline
- NIAID NIH HHS [P01 AI036535] Funding Source: Medline
Defining how cancer-associated mutations perturb signaling networks in stem/ progenitor populations that are integral to tumor formation and maintenance is a fundamental problem with biologic and clinical implications. Point mutations in RAS genes contribute to many cancers, including myeloid malignancies. We investigated the effects of an oncogenic Kras(G12D) allele on phosphorylated signaling molecules in primary c-kit(+) lin(-/low) hematopoietic stem/progenitor cells. Comparison of wild-type and Kras(G12D) c-kit(+) lin(-/low) cells shows that K-RaSG12D expression causes hyperproliferation in vivo and results in abnormal levels of phosphorylated STAT5, ERK, and S6 under basal and stimulated conditions. Whereas Kras(G12D) cells demonstrate hyperactive signaling after exposure to granulocyte-macrophage colony-stimulating factor, we unexpectedly observe a paradoxical attenuation of ERK and S6 phosphorylation in response to stem cell factor. These studies provide direct biochemical evidence that cancer stem/ progenitor cells remodel signaling networks in response to oncogenic stress and demonstrate that multi-parameter flow cytometry can be used to monitor the effects of targeted therapeutics in vivo. This strategy has broad implications for defining the architecture of signaling networks in primary cancer cells and for implementing stem cell-targeted interventions.
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