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P53 aberrations in B-CLL predict survival and are associated with in-vivo resistance to therapy


, : P53 aberrations in B-CLL predict survival and are associated with in-vivo resistance to therapy. Blood 96(11 Part 2): 174b, November 16

In B-cell chronic lymphocytic leukemia (B-CLL) mutations and/or deletions of the p53 tumor suppressor gene are observed in 8 to 15% of cases and were shown to have strong implications for the clinical course of the disease. To further evaluate the incidence and the prognostic impact of mono- and biallelic p53 alterations in B-CLL we investigated the mutational status of p53 in 114 cases with (n=13) and without a p53 deletion (n=101) as assessed by fluorescence in situ hybridization (FISH). The complete coding region (exons 2 to 11) was analyzed by polymerase chain reaction (PCR) followed by direct sequencing in the majority of cases (n=107). Due to insufficient amounts of DNA only exons 2 to 9 were analyzed in the remaining cases. The incidence of p53 alterations was 14% (16/110), of which 7 lesions were monoallelic and 9 biallelic. The distribution of stage, age and sex was similar in all groups. The median treatment-free interval (TFI) (4 vs. 27 m; p<0.01) and the median survival time (OS) (29 vs. 67 m, p<0.01) were significantly shorter in the group with p53 aberrations. Subgroup analysis showed similar median TFI and OS in the groups with biallelic and monoallelic alterations (5m vs. 2m, p=0.17, and 38m vs. 15m, p=0.13, respectively). Thus, biallelic as well as monoallelic p53 alteration predicted for shorter TFI and OS. In addition, we identified 4 patients who had no p53 alteration at the initial presentation but acquired a clonal biallelic p53 disruption within the course of the disease. All four patients showed a progressive disease and were treated with multiple chemotherapeutic regimens, including alkylating agents and fludarabine. The p53 mutation and deletion status were analyzed in follow up tumor samples before and after therapy. Interestingly, in all four cases the percentage of the B-CLL cells carrying a p53 deletion as well as the intensity of the mutated signals (compared to the residual wildtype signal) increased or became firstly detectable in the post therapy samples. Thus, a reduction of the subclone without the p53 alteration was achieved, while the subclone carrying a p53 disruption expanded despite therapy in all 4 cases. In conclusion, our data confirm the adverse prognostic impact of genetic p53 abnormalities in B-CLL. Interestingly, mono- and biallelic p53 alterations equally predicted for poor prognosis. In addition, we demonstrate in vivo resistance to therapy with alkylating agents and fludarabine of B-CLL subclones carrying a p53 disruption.

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