title: p53 abnormalities in B-cell prolymphocytic leukemia.
abstract: B-cell prolymphocytic leukemia (B-PLL) is an aggressive disorder of mature B cells with distinct clinical and pathologic features. To determine the incidence of abnormalities of p53, we analyzed 19 cases of B-PLL by DNA blot to assess loss of heterozygosity (LOH) at 17p13.3, by immunocytochemistry to assess p53 expression, and by direct DNA sequencing of polymerase chain reaction-amplified exons 5 to 9 of the p53 gene. LOH was detected in 10 of 19 (53%) cases, p53 expression was detected 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 other B-cell malignancies. Six cases exhibited missense mutations; 4 were transversions and 2 were transitions. The G:C --> A:T transition at cathepsin G dinucleotides commonly reported in p53 mutations in chronic lymphocytic leukemia (CLL) and other hematologic malignancies was observed 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. In 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 p53 mutation showed loss of germline p53 sequences. However, 3 of 10 showed no LOH by Southern blot, indicating a localized deletion around the p53 locus at 17p13.1. Five of the 10 cases with p53 mutation exhibited detectable p53 expression, including 4 cases with p53 missense mutation and 1 case with deletion. Two of 7 cases with no detectable mutation of p53 nevertheless overexpressed p53. Therefore, there was no correlation between protein expression and p53 mutation in B-PLL. Our data 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 other hematologic malignancies and may indicate that a distinct pathogenic mechanism operates in B-PLL.
authors.affiliation: Academic Department of Haematology and Cytogenetics, Royal Marsden Hospital, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Lens
authors.forename: P J
authors.initials: PJ
authors.lastname: De Schouwer
authors.forename: R A
authors.initials: RA
authors.lastname: Hamoudi
authors.forename: M
authors.initials: M
authors.lastname: Abdul-Rauf
authors.forename: N
authors.initials: N
authors.lastname: Farahat
authors.forename: E
authors.initials: E
authors.lastname: Matutes
authors.forename: T
authors.initials: T
authors.lastname: Crook
authors.forename: M J
authors.initials: MJ
authors.lastname: Dyer
authors.forename: D
authors.initials: D
authors.lastname: Catovsky
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006579:Heterozygote; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology; D015463:Leukemia, Prolymphocytic / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
chemical_list: D016159:Tumor Suppressor Protein p53