p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies

Abstract

We analyzed the prognostic value of p53 mutations for response to chemotherapy and survival in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic lymphocytic leukemia (CLL). Mutations were detected by single-stranded conformation polymorphism (SSCP) analysis of exons 4 to 10 of the P53 gene, and confirmed by direct sequencing. A p53 mutation was found in 16 of 107 (15%) AML, 20 of 182 (11%) MDS, and 9 of 81 (11%) CLL tested. In AML, three of nine (33%) mutated cases and 66 of 81 (81%) nonmutated cases treated with intensive chemotherapy achieved complete remission (CR) (P = .005) and none of five mutated cases and three of six nonmutated cases treated by low-dose Ara C achieved CR or partial remission (PR) (P = .06). Median actuarial survival was 2.5 months in mutated cases, and 15 months in nonmutated cases (P < 10(-5)). In the MDS patients who received chemotherapy (intensive chemotherapy or low-dose Ara C), 1 of 13 (8%) mutated cases and 23 of 38 (60%) nonmutated cases achieved CR or PR (P = .004), and median actuarial survival was 2.5 and 13.5 months, respectively (P < 10(-5)). In all MDS cases (treated and untreated), the survival difference between mutated cases and nonmutated cases was also highly significant. In CLL, 1 of 8 (12.5%) mutated cases treated by chemotherapy (chlorambucil and/or CHOP and/or fludarabine) responded, as compared with 29 of 36 (80%) nonmutated cases (P = .02). In all CLL cases, survival from p53 analysis was significantly shorter in mutated cases (median 7 months) than in nonmutated cases (median not reached) (P < 10(-5)). In 35 of the 45 mutated cases of AML, MDS, and CLL, cytogenetic analysis or SSCP and sequence findings showed loss of the nonmutated P53 allele. Our findings show that p53 mutations are a strong prognostic indicator of response to chemotherapy and survival in AML, MDS, and CLL. The usual association of p53 mutations to loss of the nonmutated P53 allele, in those disorders, ie, to absence of normal p53 in tumor cells, suggests that p53 mutations could induce drug resistance, at least in part, by interfering with normal apoptotic pathways in tumor cells.

Dic(17;18)(p11.2;p11.2) is a recurring abnormality in chronic lymphocytic leukaemia associated with aggressive disease

“…Our data demonstrated that dic(17;18)(p11.2;p11.2) is a novel recurrent cytogenetic abnormality in CLL associated with early age at diagnosis, accelerated disease progression, and a trend toward more refractory disease. These features are similar to previously published reports of patients with loss of p53 or del(17p13.1) alone, which found these patients to require early therapy, to have poor response to standard purine analog therapy, and have shortened survival (Fenaux et al, 1992;Wattel et al, 1994;Dohner et al, 1995;Cordone et al, 1998;Oscier et al, 2002). Within this subset of del(17p.13.)…”

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.…”