Selective pressure as an essential force in molecular evolution of myeloidleukemic clones: a view from the window of Fanconi anemia

Specific chromosomal deletions are commonly found in bone marrow cells of c hildren with Fanconi anemia (FA) whose disease has evolved to myelodysplast ic syndrome (MDS) or acute myeloid leukemia (AML). Identical deletions are found in adults with MDS/AML with a history of exposure to alkylating agent s (secondary MDS/AML). While deleted chromosomal regions likely harbor gene s encoding proteins with tumor suppressor (TS) function, such genes have no t been identified and the environmental forces by which these mutant clones are selected remain unclear. A consistent signaling abnormality in cells b earing mutations of the Fanconi anemia complementation group C (FA-C) gene (FANCC) has revealed a potential selective force. Hematopoietic progenitor cells from patients and mice with FANCC mutations are hypersensitive to the inhibitory effects of IFN gamma and TNF alpha. Consequently, clonal outgro wths in FA likely result from strong selective pressure for stem and/or pro genitor cells resistant to these inhibitory cytokines. Additional mutations that inactivate signaling pathways for these inhibitors would create a cel l with a profound proliferative advantage over its apoptosis-prone counterp arts. Here, we present preliminary evidence supporting a selection-based mo del of leukemic evolution and argue that MDS in FA patients is a de facto m odel of secondary MDS in non-FA adults.