Dynamics of clonal selection. Time and the environment are emphasized in this visualization of hematopoiesis, following the classic diagrams of clonal evolution in myelodysplasia and AML.37 (A) Cytotoxic chemotherapy produces an acute reduction in hematopoiesis because of strong cell toxicity, in which survival of a cell resistant to apoptotic signals is strongly favored. (B) In immune bone marrow failure, as in AA and hypoplastic MDS, cells resistant to immune attack will be favored, as will cells that thrive in a regenerative environment depleted of normal progenitors but rich in hematopoietic growth factors. (C) Many poorly defined factors likely influence clonal selection with aging. Remarkably, of genes identified as recurrently mutated in myeloid malignancies, limited cassettes are mutated under these environmental stresses: TP53 after chemotherapy; DNMT3A, ASXL1, and BCOR (and PIGA, not a leukemia gene) in aplastic anemia; and TET2, DNMT3A, and ASXL1 in CHIP. HSC, hematopoietic stem cell.
