The Relationship Between the Type ofbcr-ablHybrid Messenger RNA and Thrombopoiesis in Philadelphia-Positive Chronic Myelogenous Leukemia

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Abstract
Formation of the Philadelphia (Ph1) chromosome, which contains the hybrid bcr-abl gene, is thought to be the initial event in chronic myelogenous leukemia (CML). The positions of the breakpoint within the breakpoint cluster region (bcr) on the bcr-abl gene in 22 chronic-phase cases of Ph1-positive CML were determined using conventional Southern blots, and the splicing pattern were also determined the species of the fused bcr-abl mRNA in 79 CML cases using the polymerase chain-reaction procedure (RT-PCR). The location of the breakpoint within the bcr locus was assigned to one of five zones. Breakpoints in zones 1 and 2 were grouped as 5', and those in zones 3,4 and 5 as 3'. Nine patients had 5' breakpoints and 13 patients had 3' breakpoints. The platelet counts of 3' patients were significantly higher than those of 5' patients (1395 vs 274 × 109/L; p < 0.03). The megakaryocyte counts from bone marrow histological sections in 3' patients (n = 12) and 5' patients (n = 7) were 63.4/mm2 and 19.5/mm2, with a significant difference at p < 0.006. The mean number of megakaryocyte progenitor cells assayed by in vitro cloning was 128.3/2 × 105 bone marrow cells for 3' patients (n = 7) compared with 46.3 for 5' patients (n = 4). Using the RT-PCR technique, the bcr exon 2/abl exon 2 fused mRNA (b2-a2) was detected in 18 patients, the bcr exon 3/abl exon 2 fused mRNA (b3-a2) was detected in 45 patients, and both types of mRNA were detected in 16 patients. The platelet counts of patients who expressed b3-a2 mRNA or both types were significantly higher than the counts of patients who expressed only b2-a2 (813 vs 379 × 109/1; p < 0.01). The megakaryocyte counts from bone marrow histological sections in patients with b3-a2 type (n = 19) and with b2-a2 type (n = 7) were 67.1/mm2 and 27.7/mm2, respectively, with difference being significant at p < 0.02. All these findings suggest that Ph1- positive CML patients with 3' breakpoints or with b3-a2 type mRNA have higher thrombopoietic activity than patients with 5' or b2-a2 type.