[The cellular and molecular-biological studies on Philadelphia chromosome-positive acute lymphocytic leukemia]

Abstract

Philadelphia chromosome (Ph1) is detected in more than 95% of chronic myelogenous leukemia (CML) and approximately 20% of adult acute lymphocytic leukemia (ALL). In order to discriminate Ph1-positive ALL from Ph1-positive CML as a clinical entity, I studied on biological and genetic characteristics of Ph1-positive ALL cells. Two cases out of 11 Ph1-positive ALL showed hybrid leukemia phenotypes; in one hybrid case simultaneous proliferation of lymphoid and myeloid blast cells was observed and contained rearranged alleles of heavy chain genes, thus indicating that both blast cells might originate from a common precursor. Two Ph1-positive ALL cell lines (TOM-1 and ALL-MIK) were established from two patients and were investigated for their differentiation potential in vitro. Both cell lines showed the potency to differentiate into monocytic lineage cells, thus suggesting that these Ph1-positive ALL cells might reside at the stage of multipotent progenitor cell along hematopoietic cell differentiation. As to Ph1-chromosome, 4 out of 9 Ph1-positive ALL cases showed rearrangements within the classical sequence (M-bcr), similar to those in CML cases. Two out of 5 cases without rearrangement of M-bcr showed breakpoints in the first intron of the BCR gene. In the rest of 3 cases, BCR-ABL rearrangement was not detected by Southern analysis. However, a leukemic cell line established from one of these patients (TOM-1) were contained P190bcr-abl mRNA as analyzed through RT-PCR. Thus, breakpoints of the BCR gene in Ph1-positive ALL cases were heterogenous, in contrast to those of CML. Then, I investigated whether or not the activation of transforming genes other than BCR-ABL might be involved in pathogenesis of Ph1-positive ALL. Three out of 15 Ph1-negative ALL cases showed the mutations of RAS gene by the PCR. However, no activated oncogene was detected in Ph1-positive ALL cases by both DNA transfection assay and PCR.