P16 GENE HOMOZYGOUS DELETIONS IN ACUTE LYMPHOBLASTIC-LEUKEMIA

The p16 protein is a cyclin inhibitor encoded by a gene located in 9p2 1, which may have antioncogenic properties, and is inactivated by homo zygous p16 gene deletion or, less often, point mutation in several typ es of solid tumors often associated to cytogenetic evidence of 9p21 de letion. We looked for homozygous deletion and point mutation of the p1 6 gene in acute lymphoblastic leukemia (ALL), where 9p21 deletion or r earrangement are also nonrandom cytogenetic findings. Other hematologi c malignancies including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic lymphocytic leukemia (CLL), and myeloma were also studied. Homozygous deletion of the p16 gene was seen in 9 of th e 63 (14%) ALL analyzed, including 6/39 precursor B-ALL, 3/12 T-ALL, a nd 0/12 Burkitt's ALL. Three of the 7 ALL with 9p rearrangement (inclu ding 3 of the 5 patients where this rearrangement was clearly associat ed to 9p21 monosomy) had homozygous deletion compared to 5 of the 55 p atients with normal 9p (the last patient with homozygous deletion was not successfully karyotyped). Single stranded conformation polymorphis m analysis of exons 1 and 2 of the p16 gene was performed in 88 cases of ALL. including the 63 patients analyzed by Southern blot. Twenty-si x of the cases had 9p rearrangement, associated to 9p21 monosomy in at least 12 cases. A missense point mutation, at codon 49 (nucleotide 16 4), was seen in only 1 of the 88 patients. No homozygous deletion and no point mutation of the p16 gene was seen in AML, MDS, CLL, and myelo ma. Homozygous deletion of interferon alpha genes (situated close to p 16 gene in 9p21) was seen in only 3 of the 9 ALL patients with p16 gen e homozygous deletion, and none of the ALL without p16 gene homozygous deletion. Our findings suggest that homozygous deletion of the p16 ge ne is seen in about 15% of ALL cases, is not restricted to cases with cytogenetically detectable 9p deletion, and could have a pathogenetic role in this malignancy. On the other hand, p16 point mutations are ve ry rare in ALL, and we found no p16 homozygous deletions or mutations in the other hematologic malignancies studied. (C) 1995 by The America n Society of Hematology.