Genetics of myeloid leukemias.
Human leukemias are typified by acquired recurring chromosomal translocations. Cloning of these translocation breakpoints has provided important insights into pathogenesis of disease as well as novel therapeutic approaches. Chronic myelogenous leukemias (CML) are caused by constitutively activated tyrosine kinases, such as BCR/ABL, that confer a proliferative and survival advantage to hematopoietic progenitors but do not affect differentiation. These activated kinases are validated targets for therapy with selective tyrosine kinase inhibitors, a paradigm that may have broad applications in treatment of hematologic malignancies as well as solid tumors. Chromosomal translocations in acute myeloid leukemias (AML) most often result in loss-of-function mutations in transcription factors that are required for normal hematopoietic development. These latter mutations, however, are not sufficient to cause AML. The available evidence indicates that activating mutations in the hematopoietic tyrosine kinases FLT3 and c-KIT, and in N-RAS and K-RAS, confer proliferative advantage to hematopoietic progenitors and cooperate with loss-of-function mutations in hematopoietic transcription factors to cause an acute leukemia phenotype characterized by proliferation and impaired differentiation. The data supporting this hypothesis and the clinical and therapeutic implications of these observations are reviewed.
Kelly
Louise M
LM
Howard Hughes Medical Institute, Brigham and Women's Hospital, Harvard Institutes of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. lkelly@hihg.med.harvard
Gilliland
D Gary
DG
D002454:Cell Differentiation; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics*; D008954:Models, Biological; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics*; D051941:fms-Like Tyrosine Kinase 3; D018631:ras Proteins / Q000235:genetics
D011518:Proto-Oncogene Proteins; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D018631:ras Proteins