Submitted April 5, 2006
Accepted April 24, 2006
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 G Gilliland
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA, USA
Division of Oncology,Departments of Medicine & Genetics,Siteman Cancer Center,Washington University
Section of Hematology/Oncology,Department of Medicine & Cancer Research Center,University of Chicago
* Corresponding author; email: ichan{at}partners.org.
The majority of 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 4-10% of APL
patients harbor oncogenic ras mutations, we co-expressed
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 testing
the in vivo efficacy of RAS signaling pathway inhibitors
in conjunction with other targeted therapies such as
ATRA and arsenic trioxide.
