Formal proof of clonal adaptation/selection in a preclinical model of Fanconi anemia (FA). FA group C mutant cells are intrinsically hypersensitive to the apoptotic effects of TNFα, yet clonally evolved cells are resistant.^33,34 To test the hypothesis that TNF exposure would change the fitness landscape significantly enough to permit rapid clonal evolution specifically in FA stem cells, Kit⁺, lin⁻, Sca⁺ marrow cells from wild-type (WT) and Fancc^−/− mice (a murine model of FA of the C complementation group) were exposed for various periods of time (up to 35 days) to hematopoietic growth factors (HGFs) alone or to the same growth factors plus TNFα.³⁵ Cell numbers rose then declined over a period of 30 days in wild-type cell cultures and in Fancc^−/− cells exposed to HGFs alone. However, while, as expected, expansion of Fancc^−/− stem cell progeny was markedly suppressed by TNFα for 2 to 3 weeks, by late in the third week, a population of proliferating cells appeared. These cells bore clonal cytogenetic defects, were resistant to TNFα, and when transplanted into recipient mice, led to the development of acute myelogenous leukemia (AML) within approximately 4 months. Transplantation of the leukemic cells led to the development of leukemia in a second recipient mouse with a much shorter latency period.³⁵