[Diagnosis of hematological disorders by mutational analysis of oncogenes]

There is compelling evidence that leukemia arises via a multistep process. Molecular analysis of human leukemias, which are typically clonal, commonly shows multiple genetic lesions in a single leukemia including chromosomal translocations, gene amplification, and point mutations, and in several cases the mutational activation of an oncogene and the loss of a tumor suppressor gene have been found in the same leukemic cell. Accumulative evidences suggest that a number of oncogenes and tumor suppressor genes are involved in the hematopoietic tumorigenesis. These mutations can be utilized for molecular diagnosis of human hematopoietic tumors. Among them, detection of chimeric gene generated by chromosomal translocation is especially useful for molecular diagnosis. The t(3;21) (q26;q22) translocation is found usually in blastic crisis of CML and leukemias developed from MDS or hematopoietic proliferative diseases, but never in de novo acute myelocytic leukemia. This raises the possibility that the molecular event underlying the t(3;21) translocation has a critical role in progression from a preleukemic state to a leukemic state. The generation of AML1/EVI-1 chimeric gene has been demonstrated to be consistent in t(3;21)-carrying leukemias. Although target genes remain to be elucidated for both AML1 and EVI-1 as transcription factors, the AML1/EVI-1 fusion protein could work on different set of genes critical to the process of proliferation and differentiation of hematopoietic cells.