Phi - positive , bcr - negative Acute Leukemias : Clustering of Breakpoints on Chromosome 22 in the 3 ’ End of the BCR Gene First Intron

T HE PH1 CHROMOSOME, hallmark of chronic myeboid leukemia (CML), is also found in 5% to 20% of acute lymphoblastic leukemias (ALL) and in about 1% of acute nonbymphoblastic leukemias (AN LL).’ Recent studies showed that about half of the Phl-positive ALLs exhibit molecular rearrangements in the 5.8-kb breakpoint cluster region (bcr, or M-BCR-l according to a recently proposed nomenclature)2 of the BCR gene, as described in the great majority of CML,3 and produce a 210-Kd chimeric bcr-abl’ protein translated from an 8.5-kb fusion messenger RNA (mRNA) and displaying a significant tyrosine kinase activity.2 In the remaining half of Phi-positive ALLs, no bcr rearrangements are detected. However, in some of these, designated PhI-positive, bcr-negative (Phl bcr) ALLs, a new bcr-abl’ chimeric mRNA of 7.0 kb and a resultant protein of I 90 Kd were found.2 Nucleic acid sequence analysis and immunoprecipitation showed that the new fusion molecule was composed of the first exon of the BCR gene and the common exons of c-abl’, implying that the breakpoints on chromosome 22 should be localized in the first intron of the BCR gene.4 We have recently cloned 64 kb of the 5’ part of the BCR gene, including an approximately 40-kb region derived from the first intron.5 Using a panel of genomic probes, the breakpoints on chromosome 22 in six out ofseven Phl bcr acute leukemias were localized in a region of 10.8 kb, designated bcr2 (or m-BCR-l according to Gale and Goldman),2 which is 40 kb upstream of the classical bcr.5’6 During this study, we had one Phl bcr case in which no rearrangement could be detected with bcr2 probes. Here we localize the rearrangement of the BCR gene in this case and show that it is very close to that observed in another