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Philadelphia-negative chronic myelogenous leukemia with breakpoint cluster region rearrangement: molecular analysis, clinical characteristics, and response to therapy.
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1988
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Bcr RearrangementMixed-phenotype Acute LeukemiaPathologyChromosome AbnormalityTumor BiologyMyeloid NeoplasiaHematological MalignancyOncologyMolecular AnalysisHematologyClinical CharacteristicsMolecular DiagnosticsChromosome 22Cancer ResearchCell DivisionBcr GeneChromosomal RearrangementCell BiologyChromatinMalignant Blood DisorderMedicine
Northern blotting of cells from five patients revealed an 8‑kb mRNA identical to the bcr‑abl transcript, indicating a pathogenic mechanism similar to Ph‑positive CML. In seven Philadelphia‑negative CML patients, a breakpoint cluster region rearrangement was detected, and these patients exhibited clinical features and favorable responses to hydroxyurea, busulphan, or IFN‑α comparable to Ph‑positive disease, while molecular analysis showed an 8‑kb bcr‑abl–like transcript and highlighted that deletions require probes covering both 5′ and 3′ regions for accurate diagnosis and that molecular monitoring can aid therapy follow‑up.
We have detected rearrangement in the breakpoint cluster region (bcr) on chromosome 22 in cells derived from seven chronic myelogenous leukemia (CML) patients who had no cytogenetic evidence of a chromosome abnormality. These Philadelphia (Ph)-negative, bcr rearrangement-positive CML patients had clinical features and laboratory parameters that bore a strong resemblance to those of Ph-positive CML; all patients have shown a favorable response to hydroxyurea, busulphan, or alpha interferon (IFN-alpha) therapy. In one patient, because of the deletion of distal 3' sequences, detection of bcr rearrangement required a large probe that recognized proximal 5' sequences. Cells obtained from five patients were studied by Northern blotting and showed an aberrant 8 kilobase (kb) mRNA indistinguishable from the bcr-abl transcript that is felt to be a pathogenetic factor in Ph-positive CML. In three patients with a normal karyotype, bcr rearrangement was detected at the time of hematologic remission, and represented the only evidence for persistent malignancy. Our results suggest that: (1) the presence of bcr rearrangement in CML is associated with clinical features of Ph-positive disease, even in the absence of the Ph chromosome; (2) deletions occur within bcr and necessitate the use of probes covering both 5' and 3' DNA segments for accurate diagnosis; (3) molecular analysis may provide a useful approach to the follow-up of leukemia therapy in some patients; and (4) these patients respond to hydroxyurea, busulphan, and IFN-alpha therapy.