Mutant N-ras induces myeloproliferative disorders and apoptosis in bone marrow repopulated mice

Mutations that activate the N-ras oncogene are among the most frequently de tected genetic alterations in human acute myeloid leukemias (AMLs), Philade lphia chromosome-negative myeloproliferative disorders (MPDs), and myelodys plastic syndromes (MDSs). However, because hi-ms has not been shown to indu ce 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 in duce myeloid leukemia, lethally irradiated mice were reconstituted with bon e marrow (BM) cells infected with a retroviral vector carrying activated N- ras. Approximately 60% of these mice developed hematopoietic disorders, inc luding severe MPDs resembling human chronic myelogenous leukemia (CML) or A ML with differentiation (French-American-British [FAB] classification M2). Other reconstituted mice succumbed to hematopoietic defects that were patho logically 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 o f apoptosis associated with thymic atrophy and peripheral blood (PB) lympho penia was also evident in N-ras reconstituted mice. Our results are consist ent with a model in which antiproliferative effects are a primary consequen ce of hi-ms mutations and secondary transforming events are necessary for t he development of myeloid leukemia. This is the first report of an in vivo model for N-ras induced MPD and leukemia. (C) 1999 by The American Society of Hematology.