title: 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 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.
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: G
authors.initials: G
authors.lastname: Kong
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.|Institute of Physiology, National Yang-Ming University, Taipei City, Taiwan.
authors.forename: Y-I
authors.initials: YI
authors.lastname: Chang
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: A
authors.initials: A
authors.lastname: Damnernsawad
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: X
authors.initials: X
authors.lastname: You
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Pathology & Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Ranheim
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: W
authors.initials: W
authors.lastname: Lee
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.|Yonsei University College of Medicine, Seoul, Korea.
authors.forename: M-J
authors.initials: MJ
authors.lastname: Ryu
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Chang
authors.affiliation: Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA.|Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Burd
authors.affiliation: McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D011905:Genes, ras; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009196:Myeloproliferative Disorders / Q000209:etiology*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000172:deficiency* / Q000502:physiology; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)