Identification of somatic hypermutations in the TP53 gene in B-cell chronic lymphocytic leukemia.
Abnormalities of the TP53 gene are associated with a particularly severe prognosis in patients with B-cell chronic lymphocytic leukemia (B-CLL). This tumor-suppressor is mostly inactivated by the deletion of one and point mutation of the other allele and has not been previously shown to be hypermutated in B-CLL. We identified two patients whose lymphocytes showed repeatedly an extensive proportion of TP53 mutated cells by FASAY analysis (the yeast functional assay) and harbored various TP53 mutations, mostly single-base substitutions, in individual cells. The mutation targeting exhibited characteristic traits of the somatic hypermutation process. In the first patient (harboring the unmutated IgVH locus) a significant bias to point mutations at CG pairs (21/25; P=0.009), their remarkable preference for the RGYW/WRCY motives (28%) and the highest expression of the activation-induced cytidine deaminase (AID) mRNA among the 34 tested B-CLL samples. In the second patient no CG bias was observed but the targeting of point mutations into the RGYW/WRCY motives was even more prominent here (7/16; 44%). Moreover, six out of eight point mutations affecting AT pairs were localized in the WA/TW motives, which are also characteristic for the somatic hypermutations. This patient, who was IgVH-mutated, already did not express any significant amount of the AID transcript. Our findings add a new aspect to the mosaic of the p53 mutability in B-CLL.
Malcikova
J
J
Center of Molecular Biology and Gene Therapy, University Hospital Brno, Cernopolni 9, CZ-625 00 Brno, Czech Republic.
Smardova
J
J
Pekova
S
S
Cejkova
S
S
Kotaskova
J
J
Tichy
B
B
Francova
H
H
Doubek
M
M
Brychtova
Y
Y
Janek
D
D
Pospisilova
S
S
Mayer
J
J
Dvorakova
D
D
Trbusek
M
M
D003564:Cytidine Deaminase / Q000235:genetics; D016158:Genes, p53; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D008214:Lymphocytes / Q000473:pathology; D009154:Mutation; D017354:Point Mutation; D027041:Somatic Hypermutation, Immunoglobulin
D003564:Cytidine Deaminase