Relationship between p53 dysfunction, CD38 expression, andIgVH mutation in chronic lymphocytic leukemia

Abstract

Established adverse prognostic factors in chronic lymphocytic leukemia (CLL) include CD38 expression, relative lack ofIgVH mutation, and defects of theTP53 gene. However, disruption of the p53 pathway can occur through mechanisms other than TP53 mutation, and we have recently developed a simple screening test that detects p53 dysfunction due to mutation of the genes encoding either p53 or ATM, a kinase that regulates p53. The present study was conducted to examine the predictive value of this test and to establish the relationship between p53 dysfunction, CD38 expression, and IgVHmutation. CLL cells from 71 patients were examined forIgVH mutation, CD38 expression, and p53 dysfunction (detected as an impaired p53/p21 response to ionizing radiation). Survival data obtained from 69 patients were analyzed according to each of these parameters. Relative lack ofIgVH mutation (less than 5%; n = 45), CD38 positivity (antigen expressed on more than 20% of malignant cells; n = 19), and p53 dysfunction (n = 19) were independently confirmed as adverse prognostic factors. Intriguingly, all p53-dysfunctional patients and all but one of the CD38+ patients had greater than 5% IgVH mutation. Moreover, patients with p53 dysfunction and/or CD38 positivity (n = 31) accounted for the short survival of the less mutated group. These findings indicate that the poor outcome associated with having less than 5%IgVH mutation may be due to the overrepresentation of high-risk patients with p53 dysfunction and/or CD38 positivity within this group, and that CD38− patients with functionally intact p53 may have a prolonged survival regardless of the extent of IgVH mutation.