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Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 2043-2056
Mutant N-ras Induces Myeloproliferative Disorders and Apoptosis
in Bone Marrow Repopulated Mice
K.L. MacKenzie,
A. Dolnikov,
M. Millington,
Y. Shounan, and
G. Symonds
From the Department of Clinical Pharmacology and Toxicology and the
Department of Haematology, St Vincent's Hospital, Darlinghurst, New
South Wales, Australia; and the School of Physiology and Pharmacology,
University of New South Wales, Kensington, New South Wales, Australia.
Mutations that activate the N-ras oncogene are among the
most frequently detected genetic alterations in human acute myeloid leukemias (AMLs), Philadelphia chromosome-negative myeloproliferative disorders (MPDs), and myelodysplastic syndromes (MDSs). However, because N-ras has not been shown to induce these disorders in an in vivo model, the role of N-ras in the evolution of myeloid leukemia is unclear. To investigate the potential of N-ras to induce myeloid leukemia, lethally irradiated mice were reconstituted with bone marrow (BM) cells infected with a retroviral vector carrying
activated N-ras. Approximately 60% of these mice developed hematopoietic disorders, including severe MPDs resembling human chronic
myelogenous leukemia (CML) or AML with differentiation (French-American-British [FAB] classification M2). Other
reconstituted mice succumbed to hematopoietic defects that were
pathologically similar to human MDSs. The latter disorders appeared to
be due to a myeloid impairment that was demonstrated by enumeration of day-12 colony-forming units-spleen (CFU-S) and by in vitro
colony assays. A high level of apoptosis associated with thymic atrophy and peripheral blood (PB) lymphopenia was also evident in N-ras reconstituted mice. Our results are consistent with a model in which
antiproliferative effects are a primary consequence of N-ras mutations and secondary transforming events are necessary for the
development of myeloid leukemia. This is the first report of an in vivo
model for N-ras induced MPD and leukemia.
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