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  • Original Article
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Transcriptional control and signal transduction, cell cycle

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

Abstract

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 KrasG12D/− 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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Acknowledgements

We thank the University of Wisconsin Carbone Comprehensive Cancer Center (UWCCC) for use of its Shared Services to complete this research. This work was supported by R01 grants R01CA152108 and R01HL113066, and a Scholar Award from the Leukemia & Lymphoma Society to JZ and R01 GM096060 to YX. This work was also supported in part by NIH/NCI P30 CA014520—UW Comprehensive Cancer Center Support.

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Correspondence to J Zhang.

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Kong, G., Chang, YI., Damnernsawad, A. et al. Loss of wild-type Kras promotes activation of all Ras isoforms in oncogenic Kras-induced leukemogenesis. Leukemia 30, 1542–1551 (2016). https://doi.org/10.1038/leu.2016.40

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