Molecular genetics of human leukemias: new insights into therapy.
Significant advances have occurred in understanding the molecular pathogenesis of human leukemias. Analysis of patient karyotypes reveals that nonrandom, somatically acquired translocations and inversions occur in most acute myeloid leukemias. Among these, fusion oncogenes have been identified that utilize similar signal transduction pathways and transcriptional activation pathways to mediate their leukemogeneic effect. In chronic myeloid leukemia (CML), both in vitro and in vivo animal studies show that BCR-AB expression leads to clinical manifestations of CML, demonstrating that BCR-AB and its fusion proteins are central mediators of myeloid proliferation and transformation in these malignancies. In other CML syndromes (chronic myelomonocytic leukemia, atypical CML), cloning of chromosomal translocation breakpoints has identified a spectrum of constitutively activated tyrosine kinases. These tyrosine kinase fusions alone apparently are both necessary and sufficient to recapitulate the disease phenotype in the murine model. In contrast, acute myelogenous leukemia (AML) is typified by chromosomal translocations involving transcription factors needed for normal myeloid differentiation. The functional consequence of translocations is loss of function of these transcription factors, resulting in impaired myeloid differentiation. However, these alone are not sufficient to cause acute leukemia; evidence strongly supports the hypothesis that second mutations are required. Data suggest a multistep pathogenesis for AML in which class I mutations, such as activating point mutations in receptor tyrosine kinases (eg, FLT3 and c-KIT), provide a proliferative and/or survival signal to hematopoietic progenitors. Class II mutations are those targeting hematopoietic transcription factors and serving primarily to impair differentiation and subsequent apoptosis. Together, these mutations result in leukemic cells capable of proliferation and survival but not differentiation. The clinical and therapeutic implication is that it may be possible to target both classes of mutations using selected or screened small-molecule inhibitors. Insights gained from molecular genetic analysis of AML provide the basis for a rational, targeted therapeutic approach.
Gilliland
D Gary
DG
Howard Hughes Medical Institute, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002869:Chromosome Aberrations; D006801:Humans; D007621:Karyotyping; D007938:Leukemia / Q000209:etiology / Q000235:genetics* / Q000628:therapy*; D008967:Molecular Biology; D009154:Mutation