title: Oncogenic K-ras cooperates with PML-RAR alpha to induce an acute promyelocytic leukemia-like disease.
abstract: Most patients with acute promyelocytic leukemia (APL) express PML-RAR alpha, the fusion product of t(15;17)(q22;q11.2). Transgenic mice expressing PML-RAR alpha 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 alpha 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.
authors: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA. iris_chan@dfci.harvard.edu
authors: Iris T
authors: IT
authors: Chan
authors: Jeffery L
authors: JL
authors: Kutok
authors: Ifor R
authors: IR
authors: Williams
authors: Sarah
authors: S
authors: Cohen
authors: Sandra
authors: S
authors: Moore
authors: Hirokazu
authors: H
authors: Shigematsu
authors: Timothy J
authors: TJ
authors: Ley
authors: Koichi
authors: K
authors: Akashi
authors: Michelle M
authors: MM
authors: Le Beau
authors: D Gary
authors: DG
authors: Gilliland