Chronic myelogenous leukemia is identified by the presence of the Philadelphia chromosome translocation leading to a bcr-abl chimeric gene in all patients. However, the bcr-abl translocation in and of itself does not completely explain the phenotype of the disease, since patients with CML are clinically stable for years before they develop a more fulminant and acute leukemia. Furthermore, many in vitro and in vivo experiments suggest that the bcr-abl fusion protein itself does not fully account for the phenotype of the disease, and additional genetic alterations are necessary. In work supported by this grant, we have analyzed myeloid progenitor cells from the bone marrow of CML patients, and found that progenitor cells lacking the bcr-abl translocation have undergone monoclonal expansion, suggesting that something in addition to the bcr-abl translocation is an early event in abnormal myeloid cell proliferation. We have recently discovered two genes that undergo genomic imprinting, or allele-specific expression depending upon the parent of origin, the fist direct molecular evidence for such genes in man. We have also found that this imprint is relaxed in Wilms tumors, a childhood kidney cancer, suggesting a novel mutational mechanism of carcinogenesis. Haas et al have recently provided cytogenetic evidence that bcr and abl are imprinted in man. They observed that the chromosome 22 containing the bcr gene in the Philadelphia chromosome translocation is of maternal origin, and the chromosome 9 containing the abl gene is of paternal origin. The full implications of this startling observation have not yet been determined, but they do suggest that Haas' observations in CML are related to ours in Wilms tumor. Furthermore, our data and Haas' together suggest that disturbances in genetic imprinting could represent a genetic alteration in CML that has been previously unrecognized. In order to determine whether genomic imprinting plays a role in the regulation of normal bcr and abl, or in the pathogenesis of CML, we will perform molecular studies to define transcribed polymorphisms in bcr and abl. We will then determine whether these genes show parental-specific monoallelic expression in normal cells. We will determine whether these genes show monoallelic expression in leukemic cells, or whether the bcr- abl transcript is co-expressed with normal bcr and/or normal abl. We also will determine whether these genes show mono or biallelic expression in myeloid progenitor cells from leukemic patients. If bcr or abl is imprinted in normal cells, we will determine whether genomic imprinting is relaxed in CML, and whether this relaxation can be correlated with clinically meaningful parameters such as response to treatment or remission duration. Finally, we will continue our analysis of monoclonal expansion of nonleukemic myeloid progenitor cells, and we will determine the relationship of this expansion to patient subpopulations with CML, as well as to genomic imprinting.
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