FREQUENT ABERRATION OF FHIT GENE-EXPRESSION IN ACUTE LEUKEMIAS

We analyzed the mRNA expression of the FHIT gene by reverse transcript ion-PCR (RT-PCR) in 54 cases of acute 14 lymphoblastic leukemia (ALL; 11 cases of T-cell ALL [T-ALL] and 43 cases of non-T-ALL) and 40 cases of acute myeloid leukemia (AML). In 46% of the ALL cases and 55% of t he AML, cases, FHIT expression was absent or markedly decreased. Only abnormal short bands were detected in 30% of the ALL cases and 5% of t he AML cases. Eighteen of 19 abnormal transcripts had the same fusion of exons 2-7, and all lacked the starting codon in exon 5. No obvious normal-sized PCR products were detected in cases exhibiting abnormal t ranscripts. These findings suggest that the expression of functional F HIT protein was lost in the majority of ALL (76%) and ARIL (60%) cases . Differential quantitative PCR of exons 3-9 of the FHIT gene and RT-P CR of the PTPRG gene, which is centromeric to the FHIT gene, showed th e presence of the target sequences. Fluorescence in situ hybridization analysis using probes covering exons 5 and 8 revealed no difference i n the signal patterns between leukemia and normal cells, showing one o r two signal doublets in more than 90% of nuclei, and indicated that g ross segments of the FHIT gene were not homozygously deleted in these cases. A small number of transcripts with an aberrant fusion between e xons 2 and 7 were detected by RT-PCR in the bone marrow cells from fou r healthy individuals. Granulocytes, lymphocytes, and monocytes in the bone marrow cells of a healthy individual contained transcripts with the same fusion. This unique fusion of exons 2 and 7 might be preferen tially seen in either neoplastic or normal hematopoietic cells, regard less of their lineage. The finding that FHIT expression was abolished in the majority of leukemia cases might support the hypothesis that th e FHIT gene acts as a tumor suppressor, at least in leukemia.