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Blood, 1 September 2006, Vol. 108, No. 5, pp. 1708-1715.
Prepublished online as a Blood First Edition Paper on May 4, 2006; DOI 10.1182/blood-2006-04-015040.
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NEOPLASIA
Oncogenic K-ras cooperates with PML-RAR to induce an acute promyelocytic leukemia-like disease
Iris T. Chan,
Jeffery L. Kutok,
Ifor R. Williams,
Sarah Cohen,
Sandra Moore,
Hirokazu Shigematsu,
Timothy J. Ley,
Koichi Akashi,
Michelle M. Le Beau, and
D. Gary Gilliland
From the Division of Hematology, Department of Medicine and the Department of Pathology, Brigham and Women's Hospital, and the Howard Hughes Medical Institute, Harvard Medical School, Boston, MA; the Department of Medical Oncology and the Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA; the Department of Pathology, Emory University School of Medicine, Atlanta, GA; the Division of Oncology, Departments of Medicine and Genetics, Siteman Cancer Center, Washington University School of Medicine, St Louis, MO; the Section of Hematology/Oncology, and the Department of Medicine and Cancer Research Center, University of Chicago, IL.
Most patients with acute promyelocytic leukemia (APL) express PML-RAR , the fusion product of t(15;17)(q22;q11.2). Transgenic mice expressing PML-RAR develop APL with long latency, low penetrance, and acquired cytogenetic abnormalities. Based on observations that 4% to 10% of APL patients harbor oncogenic ras mutations, we coexpressed oncogenic K-ras from its endogenous promoter with PML-RAR to generate a short-latency, highly penetrant mouse model of APL. The APL disease was characterized by splenomegaly, leukocytosis, extramedullary hematopoiesis (EMH) in spleen and liver with an increased proportion of immature myeloperoxidase-expressing myeloid forms; transplantability to secondary recipients; and lack of cytogenetic abnormalities. Bone marrow cells showed enhanced self-renewal in vitro. This model establishes a role for oncogenic ras in leukemia pathogenesis and thus validates the oncogenic RAS signaling pathway as a potential target for therapeutic inhibition in leukemia patients. This mouse model should be useful for investigating signaling pathways that promote self-renewal in APL and for testing the in vivo efficacy of RAS signaling pathway inhibitors in conjunction with other targeted therapies such as ATRA (all trans retinoic acid) and arsenic trioxide.
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