Journal
LEUKEMIA
Volume 30, Issue 7, Pages 1542-1551Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2016.40
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Funding
- R01 grants [R01CA152108, R01HL113066]
- Leukemia AMP
- Lymphoma Society [R01 GM096060]
- NIH/NCI-UW Comprehensive Cancer Center Support [P30 CA014520]
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Despite the well-established role of oncogenic RAS in promoting tumor formation, whether and how wild-type (WT) Ras inhibits tumorigenesis under physiological conditions remains controversial. Here, we show that in a fraction of endogenous oncogenic Kras-induced hematopoietic malignancies, including acute T-cell lymphoblastic leukemia/lymphoma (T-ALL) and myeloproliferative neoplasm (MPN), WT Kras expression is lost through epigenetic or genetic mechanisms. Using conditional Kras(G12D/-) mice, we find that WT Kras deficiency promotes oncogenic Kras-induced MPN, but not T-ALL, in a cell-autonomous manner. Loss of WT Kras rescues oncogenic Kras-mediated hematopoietic stem cell depletion and further enhances granulocyte-macrophage colony-stimulating factor signaling in myeloid cells expressing oncogenic Kras. Quantitative signaling studies reveal that oncogenic Kras but not oncogenic Nras leads to cross-activation of WT Ras, whereas loss of WT Kras further promotes the activation of all Ras isoforms. Our results demonstrate the tumor suppressor function of WT Kras in oncogenic Kras-induced leukemogenesis and elucidate its underlying cellular and signaling mechanisms.
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