title: The stem cell fitness landscape and pathways of molecular leukemogenesis.
abstract: The relative risk of clonal evolution to either myelodysplasia (MDS) or acute myelogenous leukemia (AML) is high in patients with chronic bone marrow failure. From 10 to 20% of acquired aplastic anemia survivors will develop clonal evolution within the decade following their diagnosis as will 40% of patients with some of the inherited bone marrow failure syndromes. Studies on bone marrow failure states have provided some perspective on molecular pathogenesis of marrow failure and have also provided insights on the adaptive nature of clonal evolution. We review the scientific evidence validating this model, emphasize the importance of the fitness landscape in the stem cell pool, outline the clinical and investigative implications of the model, suggest that the lack of fitness in the starting pool accounts for the phenomenon of oncogene addiction, promote the value of the model for the evaluation of prevention strategies, and argue that experiments focusing attention on the relative phenotypes of neoplastic stem cell clones and pools of unfit stem cells from which they evolved will provide a useful paradigm of carcinogenesis in general.
authors.affiliation: Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, Oregon 97239, USA. grover@ohsu.edu
authors.forename: Grover C
authors.initials: GC
authors.lastname: Bagby
authors.forename: Angela G
authors.initials: AG
authors.lastname: Fleischman
mesh_terms: D000741:Anemia, Aplastic; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D016207:Cytokines / Q000378:metabolism; D056084:Genetic Fitness / Q000235:genetics*; D006457:Hemoglobinuria, Paroxysmal / Q000150:complications / Q000473:pathology; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000473:pathology*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009190:Myelodysplastic Syndromes / Q000209:etiology / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010641:Phenotype; D012641:Selection, Genetic
chemical_list: D016207:Cytokines; D053614:Janus Kinase 2