title: Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder.
abstract: RAS mutations are common in myeloid malignancies; however, it is not known whether oncogenic RAS can initiate leukemia. We show that expressing mutant K-Ras(G12D) protein from the endogenous murine locus rapidly induces a fatal myeloproliferative disorder with 100% penetrance characterized by tissue infiltration, hypersensitivity to growth factors, and hyperproliferation. Hematopoietic cells from diseased mice demonstrated increased levels of Ras-GTP, but effector kinases were not constitutively phosphorylated and responded normally to growth factors. Oncogenic RAS is sufficient to initiate myeloid leukemogenesis in mice, and this provides an in vivo system for biologic and preclinical studies.
authors.affiliation: Department of Pediatrics, University of California, San Francisco, CA 94143, USA.
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Braun
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
authors.forename: Namie
authors.initials: N
authors.lastname: Kong
authors.forename: Doan T
authors.initials: DT
authors.lastname: Le
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: Jacob
authors.initials: J
authors.lastname: Rozmus
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.forename: Tyler E
authors.initials: TE
authors.lastname: Jacks
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Shannon
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D005434:Flow Cytometry; D011905:Genes, ras; D007621:Karyotyping; D051379:Mice; D009196:Myeloproliferative Disorders / Q000473:pathology*