P53 protein overexpression in bone marrow biopsies from chronic lymphocytic leukaemia is associated with TP53 deletion and resistance to fludarabine

Abstract

Abnormalities of the TP53 gene in chronic lymphocytic leukaemia (CLL) are associated with large cell transformation, short survival and resistance to purine analogue therapy. Deletion of one allele and somatic mutation of the remaining allele have been described as the main mechanism of TP53 inactivation in CLL, but its relationship with p53 protein expression remains unclear. We studied 103 CLL patients using fluorescence in situ hybridisation (FISH) to detect allelic loss at chromosome 17p and immunohistochemistry (IHC) to test for p53 protein overexpression. TP53 deletion (≥10% of cells) was found in 21 cases (20.4%) and no deletion in 82 (79.6%). By IHC, 16 cases (15.5%) showed p53 protein expression and 87 (84.5%) were negative. There was a good correlation between FISH and IHC in 86 cases (83.5%; p < 0.001) and these comprised ten cases positive for both assays and 76 negative cases. The remaining 17 cases had discrepant results: 11 cases showed TP53 deletion and were p53 negative, and six cases had strong expression of protein and no TP53 deletion (FISH). Seventy-two patients (70%) received fludarabine. The majority (86%) of patients without abnormalities of TP53 responded to fludarabine and only eight cases were resistant. Within the rest, all patients positive with both methods were refractory, 60% of cases with overexpression without deletion and 40% of cases with deletion without protein overexpression were non-responders to fludarabine. Our findings indicate that IHC is a simple method and provides useful complementary information to FISH analysis for the evaluation of TP53 dysfunction. Both methods can be carried routinely to identify patients with a high chance to be resistant to fludarabine containing regimens (p = 0.0003).