MOLECULAR CHARACTERIZATION OF 16P DELETIONS ASSOCIATED WITH INVERSION-16 DEFINES THE CRITICAL FUSION FOR LEUKEMOGENESIS

The inversion of chromosome 16 [inv(16)] in acute myeloid leukemia (AM L) is associated with a p-arm deletion in a subset of patients. The in version results in two fusion genes: 5'-CBFB/MYH11-3' on 16p and 5'-MY H11/CBFB-3' on 16q. We have studied cells from 42 patients with inv(16 ) (38 patients) or t(16; 16) (four patients) to define the frequency a nd characteristics of the deletion further. Using fluorescence in situ hybridization (FISH) with probes from cosmids, cosmid contigs, and ye ast artificial chromosomes (YACs), we found that six patients with inv (16) had a deletion of between 150 and 350 kb centromeric to the p-arm inversion breakpoint cluster region (p-ibc). This region was shown to contain the 5' portion of the myosin heavy chain (MYH11) gene. YACs c ontaining the p-ibc, which had been useful as FISH probes in the diagn osis of inv(16), detected the inversion in deletion as well as nondele tion patient cells. Thus, the deleted region identified in patients is entirely contained within the human genomic content of the YACs. Sout hern blot experiments using probes flanking the p-ibc indicated that t he deletion removes segments within 10 kb centromeric of the p-ibc. Re verse transcription-polymerase chain reaction (RT-PCR) using primers f rom the 5' region of CBFB and the 3' region of MYH11 (distal to the p- ibc) produced the 5'-CBFB/MYH11-3' chimeric transcript in inv(16)/del patients. These data confirm that the 5'-CBFB/MYH11-3' chimeric transc ript, rather than the reciprocal 5'-MYH11/CBFB-3', is the critical pro duct for chromosome 16-related leukemogenesis. (C) 1995 by The America n Society of Hematology.