Loss of wild-type Kras promotes activation of all Ras isoforms in oncogenic Kras-induced leukemogenesis

G. Kong, Y. I. Chang, A. Damnernsawad, X. You, J. Du, E. A. Ranheim, W. Lee, M. J. Ryu, Y. Zhou, Y. Xing, Q. Chang, C. E. Burd, J. Zhang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


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.

Original languageEnglish
Pages (from-to)1542-1551
Number of pages10
Issue number7
StatePublished - 1 Jul 2016


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