P53 ABNORMALITIES IN B-CELL PROLYMPHOCYTIC LEUKEMIA

B-cell prolymphocytic leukemia (B-PLL) is an aggressive disorder of ma ture B cells with distinct clinical and pathologic features, To determ ine the incidence of abnormalities of p53, we analyzed 19 cases of B-P LL by DNA blot to assess loss of heterozygosity (LOH) at 17p13.3, by i mmunocytochemistry to assess p53 expression, and by direct DNA sequenc ing of polymerase chain reaction-amplified exons 5 to 9 of the p53 gen e. LOH was detected in 10 of 19 (53%) cases, p53 expression was detect ed in 8 of 17 (47%), and p53 mutations were detected in 10 of 19 (53%) cases. The pattern of mutations was distinct from that observed in ot her B-cell malignancies. Six cases exhibited missense mutations; 4 wer e transversions and 2 were transitions. The G:C-->A:T transition at ca thepsin G dinucleotides commonly reported in p53 mutations in chronic lymphocytic leukemia (CLL) and other hematologic malignancies was obse rved in only 1 case of B-PLL. Three cases exhibited deletions (ranging from 3 to 35 bp in length) and one case exhibited a 2-bp insertion, I n 1 case, a 27-bp deletion resulted in the expression of a p53 protein lacking 9 amino acids from the DNA binding region. All samples with p 53 mutation showed loss of germline p53 sequences. However, 3 of 10 sh owed no LOH by Southern blot, indicating a localized deletion around t he p53 locus at 17p13.1. Five of the 10 cases with p53 mutation exhibi ted detectable p53 expression, including 4 cases with p53 missense mut ation and 1 case with deletion. Two of 7 cases with no detectable muta tion of p53 nevertheless overexpressed p53 Therefore, there was no cor relation between protein expression and p53 mutation in B-PLL. Our dat a indicate that the overall abnormalities of p53 occurred in 14 of 19 (75%) cases of B-PLL. The frequency of p53 mutation (53%) in B-PLL is the highest reported in B-cell malignancies and may be responsible for the frequent resistance to therapy of this disease. in addition, the pattern of p53 mutation was different from that observed in CLL and ot her hematologic malignancies and may indicate that a distinct pathogen ic mechanism operates in B-PLL. (C) 1997 by The American Society of He matology.