p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias

Abstract

Conventional cytogenetic analysis in B-cell chronic lymphocytic leukemia (B-CLL) has been very difficult, and the prognostic significance of specific chromosome aberrations is under discussion. Recent improvements in fluorescence in situ hybridization (ISH) techniques have provided an alternative approach for the detection of chromosome aberrations. Here, an interphase cytogenetic study was performed to analyze the incidence and prognostic significance of a p53 gene deletion in B-CLL and related disorders. We studied mononuclear cells from 100 patients with chronic B-cell leukemias [B-CLL, 90 patients; B-prolymphocytic leukemia (B-PLL), 7; Waldenstrom's macroglobulinemia (WM), 3] by fluorescence ISH with a genomic p53 DNA probe. In a subset of patients, additional G-banding analysis and single strand conformation polymorphism (SSCP) analysis was performed. Seventeen of the 100 patients [17%; B-CLL, 11 of 90 (12%); WM, 1 of 3; B-PLL, 5 of 7] exhibited a monoallelic p53 gene deletion by ISH. G- banding analysis demonstrated abnormalities of chromosome 17 in 13 of these 17 patients, all leading to loss of band 17p13. SSCP analysis showed aberrant bands in 9 of 14 patients with a p53 gene deletion. None of 12 patients with a p53 gene deletion compared with 20 of 36 patients (56%) without a deletion responded to therapy with fludarabine or pentostatin (P < .001). The difference in survival probabilities from the time of diagnosis and from the start of treatment with purine analogs between the two groups was highly significant (P < .001). In multivariate analysis, p53 gene deletion was the strongest prognostic factor for survival. In conclusion, p53 gene deletion predicts for non- response to therapy with purine analogs and for poor survival in chronic B-cell leukemias.

Flavopiridol circumvents Bcl‐2 family mediated inhibition of apoptosis and drug resistance in B‐cell chronic lymphocytic leukaemia

“…It may be particularly useful in the treatment of patients who are resistant to standard chemotherapy as it appears not only to mediate its effect through a p53-independent pathway but also seems to circumvent the Bcl-2 family mediated inhibition of apoptosis commonly seen in B-CLL. In the context of previous findings that have demonstrated a link between p53 mutation, failed apoptosis, non-responsiveness to therapy and poor prognosis in B-CLL (El Rouby et al, 1993;Wattel et al, 1994;Dohner et al, 1995), flavopiridol represents a relevant and timely addition to the chemotherapeutic arsenal for the treatment of this condition.…”

The effect of p53 dysfunction on purine analogue cytotoxicity in chronic lymphocytic leukaemia

“…The modest contribution of p53 to the nucleoside-induced killing of CLL cells suggests that the poor clinical response to nucleoside therapy observed in CLL patients with p53 abnormalities (Wattel et al, 1994;Dohner et al, 1995) is unlikely to be due to nucleoside resistance at the time of diagnosis. A more likely scenario is that the genomic instability associated with p53 dysfunction (Ko & Prives, 1996) facilitates the evolution during the course of the disease of CLL cell clones (including large-cell transformations (Lens et al, 1997)) that have become resistant to nucleosides for reasons not directly connected with p53.…”

“…It is now clear that CLL patients with p53 gene abnormalities have a short survival and respond poorly to therapy with purine analogues (Wattel et al, 1994;Dohner et al, 1995). However, the cellular basis for this important clinical observation is far from clear.…”

A prognostic model for survival in chronic lymphocytic leukaemia based on p53 expression

“…The rate of p53 gene mutation has been reported to be relatively low in CLL, being more frequently mutated in people with rapidly progressive or variant disease (Gaidano et al, 1991;Fenaux et al, 1992;Gandini et al, 1994;De Angeli et al, 2000). Mutations in the p53 gene are associated with patients who have CLL with both cytotoxic drug resistance, which is not multidrug resistance (MDR) mediated, and a poor response to purine analogues, which are the most active anti-CLL agents available (el Rouby et al, 1993;Dohner et al, 1995;O'Brien et al, 2001). Detection of p53 gene mutations is complex, relatively expensive and difficult to integrate into routine practice.…”