| Budget Amount *help |
¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1988: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1987: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Research Abstract |
Molecular analyses of bcr and abl genes and transforming genes have been carried out in Philadelphia chromosone(Ph^1)-positive leukemia. Southern blot analysis of bcr rearrangement demostrated that all CML cases have breakpoints culustered on introns among either bcr exson 2, 3 or 4. On the other hand, Ph^1-positive ALL cases showed heterogenity of chromosome 22g 21 breakpoints, with half of the cases showing no bcr rearrangement. Northern blot analysis of polyadenylated RNA showed approximately 8.5-kb bcr-abl hybrid mRNA in CML cases. In 2 Ph^1-positive ALL cases with no bcr rearrangement (Ph^<1+>, bcr^- ALL), the novel abl mRNA were seen in the position of approximately 7.5-kb and 7.3-kb respectively, but signal of mRNA was not seen in that position by Norther blot with bcr cDNA probe that contained bcr exson 1 and a part of exson 2. These results are compatible to Herrmans's report that in Ph^<1+> bcr^- ALL the breskpoints are present within the intron between the bcr gene exson 1 a
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nd 2 at least 40-kb upstream of the bcr lows. Ph^1-positive ALL cells showed the phenotypical and genotypical character as Pro-B cells. However, in Ph^<1+>, bcr^- ALL cases, one case had simultaneous proliferation of the lymphoid blasts and myeloblast and the leukemic cells of other one case showed the myeloid defferentiation in vitro, thus suggesting that P190 abl kinase, supeculated to be specific to Ph^<1+> bcr^- ALL play a role in the proliferation of myeloid cells and further may be associated with aute process rather than chronic process in ltukemogenesis. The tyrosine kinase activity of CML cells and Ph^<1+>, bcr^- ALL cells were augmented in cytozol fraction, different from other types of leukemias. This result may be related to the membrane-phobic character of P210 bcr-abl kinase. Furthermore, we have analyzed the genetic events in transformation to blast crisis from CML in chronic phase. No obvious difference was not seen between the breakpoints within bcr and the transformation to crisis. CML in crisis showed the augmented expression of 8.5-kb bcr-abl mRNA when compared with those in chrnoc phase. in DNA transfection assay using N1H3T3 cells, activated N-ras genes were detected in 2 of 7 cases of CML in crisis. These results suggest that in addition to augementation of abl gene expression, active transforming genes including ras family genes may plat an important role in giving rise to gransformation to blast crisis. Less
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