Quantitative effects of Nf1 inactivation on in vivo hematopoiesis

The NF1 tumor-suppressor gene is frequently inactivated in juvenile myelomo nocytic leukemia, and Nf1 mutant mice model this myeloproliferative disorde r (MPD). Competitive repopulation assays were performed to quantify the pro liferative advantage of Nf1(-/-) hematopoietic cells in vivo. Nf1 mutant st em cells demonstrated a growth advantage that was greatest in myeloid linea ge cells and least pronounced in T lymphocytes. Surprisingly, although low numbers of Nf1-deficient cells consistently outcompeted wild-type cells, le vels of chimerism were stable over months of observation, and MPD was not o bserved unless threshold numbers of mutant cells were injected. These data showing that normal competitor cells can strongly modulate the growth of mu tant populations in vivo have general implications for modeling cancer in t he mouse. In particular, strains in which cancer-associated mutations are e xpressed in fields of target cells may not accurately model early events in tumorigenesis because they eliminate the requirement for a mutant clone to outcompete resident normal cells.