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*

*此作品的通信作者

研究成果: Article同行評審

32 引文 斯高帕斯(Scopus)

摘要

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.

原文English
頁(從 - 到)1542-1551
頁數10
期刊Leukemia
30
發行號7
DOIs
出版狀態Published - 1 7月 2016

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