title: Selective pressure as an essential force in molecular evolution of myeloid leukemic clones: a view from the window of Fanconi anemia.
abstract: Specific chromosomal deletions are commonly found in bone marrow cells of children with Fanconi anemia (FA) whose disease has evolved to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Identical deletions are found in adults with MDS/AML with a history of exposure to alkylating agents (secondary MDS/AML). While deleted chromosomal regions likely harbor genes encoding proteins with tumor suppressor (TS) function, such genes have not been identified and the environmental forces by which these mutant clones are selected remain unclear. A consistent signaling abnormality in cells bearing 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 IFNgamma and TNFalpha. Consequently, clonal outgrowths in FA likely result from strong selective pressure for stem and/or progenitor cells resistant to these inhibitory cytokines. Additional mutations that inactivate signaling pathways for these inhibitors would create a cell with a profound proliferative advantage over its apoptosis-prone counterparts. Here, we present preliminary evidence supporting a selection-based model of leukemic evolution and argue that MDS in FA patients is a de facto model of secondary MDS in non-FA adults.
authors.affiliation: Department of Molecular and Medical Genetics, Oregon Cancer Center, Oregon Health Sciences University, Portland, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Lensch
authors.forename: R K
authors.initials: RK
authors.lastname: Rathbun
authors.forename: S B
authors.initials: SB
authors.lastname: Olson
authors.forename: G R
authors.initials: GR
authors.lastname: Jones
authors.forename: G C
authors.initials: GC
authors.lastname: Bagby
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D002869:Chromosome Aberrations / Q000235:genetics; D002999:Clone Cells / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics; D019143:Evolution, Molecular; D005199:Fanconi Anemia / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007951:Leukemia, Myeloid / Q000150:complications / Q000235:genetics / Q000473:pathology*; D008957:Models, Genetic; D009190:Myelodysplastic Syndromes / Q000150:complications / Q000235:genetics / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics; D012641:Selection, Genetic
chemical_list: D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D010750:Phosphoproteins