Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder

doi:10.1073/pnas.0307203101

Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder

Departments of ^*Pediatrics and ^‡Laboratory Medicine and ^∥Comprehensive Cancer Center, University of California, San Francisco, CA 94143; ^†Abramson Center for Cancer Research, University of Pennsylvania, Philadelphia, PA 19104; ^§Section of Hematology/Oncology, Department of Medicine and Cancer Research Center, University of Chicago, Chicago, IL 60637; and ^¶Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139

Communicated by Owen N. Witte, David Geffen School of Medicine, University of California, Los Angeles, CA, November 5, 2003 (received for review October 23, 2003)

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.

Footnotes

↵ ** To whom correspondence should be addressed at: University of California, 513 Parnassus Avenue, HSE 302, San Francisco, CA 94143. E-mail: kevins{at}itsa.ucsf.edu.
Abbreviations: MPD, myeloproliferative disorder; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; JMML, juvenile myelomonocytic leukemia; pIpC, polyinosinic–polycytidilic acid; GM-CSF, granulocyte/macrophage colony-stimulating factor; MAP, mitogen-activated protein; ERK, extracellular signal-related kinase; MEK, MAP/ERK kinase; CML, chronic myeloid leukemia.