AID protein expression in chronic lymphocytic leukemia/small lymphocytic lymphoma is associated with poor prognosis and complex genetic alterations

Abstract

The biological behavior of chronic lymphocytic leukemia and small lymphocytic lymphoma is unpredictable. Nonetheless, non-mutated IgV H gene rearrangement, ATM (11q22-23) and p53 (17p13) deletion are recognized as unfavorable prognosticators in chronic lymphocytic leukemia. The mRNA expression of activation-induced cytidine deaminase (AID), an enzyme indispensable for somatic hypermutation processes, was claimed to be predictive of non-mutated chronic lymphocytic leukemia cells in blood. Here, we evaluated AID protein expression compared with known molecular and immunohistochemical prognostic indicators in 71 chronic lymphocytic leukemia/small lymphocytic lymphoma patients using a tissue microarray approach. We found AID heterogeneously expressed in tumor cells as shown by colocalization analysis for CD5 and CD23. Ki-67 positive paraimmunoblasts of the proliferation centers displayed the highest expression. This observation is reflected by a significant association of AID positivity with a high proliferation rate (P ¼ 0.012). ATM deletion was detected in 10% (6/63) of patients and p53 deletion in 19% (13/67) of patients. Moreover, both ATM (P ¼ 0.002) and p53 deletion (P ¼ 0.004) were significantly associated with AID. IgV H gene mutation was seen in 45% (27/60) of patients. Twenty-five percent (17/69) of patients with AID-positive chronic lymphocytic leukemia/small lymphocytic lymphoma displayed a shorter survival than AID-negative chronic lymphocytic leukemia/small lymphocytic lymphoma patients (61 vs 130 months, P ¼ 0.001). Although there was a trend, we could not show an association with the IgV H gene mutation status. Taken together, our study shows that AID expression is an indicator of an unfavorable prognosis in chronic lymphocytic leukemia/small lymphocytic lymphoma patients, although it is not a surrogate marker for the IgV H status. Furthermore, the microenvironment of proliferation centers seems to influence AID regulation and might be an initiating factor in its transformation.

Duodenal follicular lymphoma lacks AID but expresses BACH2 and has memory B-cell characteristics

“…On the other hand, AID is associated with lymphomagenesis and AID expression is related to poor prognosis in several B-cell lymphoma subtypes. 9,23,24 We do not have sufficient data for long-term follow-up of patients with duodenal FL, but based on these reports, we suggest that BACH2 expression and lack of AID expression might limit the tumor stage and lead to better prognosis in duodenal FL.…”

“…For AID expression in tumor follicles, samples with 5% or more expressing cells were scored as positive as previously described. 9 Ki-67-positive cells were counted in tumor follicles. CD21 expression patterns were classified as follows: nodal (430% positive cells); intermediate (5-30% positive cells); and duodenal (o5% positive cells and FDC located at the periphery of tumor follicles).…”

New developments in the pathology of malignant lymphoma: a review of the literature published from October 2009 to January 2010

“…Leuenberger et al [64] looked at AID protein expression in 71 CLL patients but could not confirm that it is related to mutational status. Although it has prognostic impact in this study, it is unclear whether it is independent of known prognostic factors.…”

Genetics of Chronic Lymphocytic Leukemia: Practical Aspects and Prognostic Significance

“…AID expression has been considered to be predictive for CLL with unmutated IGVH status (Palacios et al, 2010). However, in other reports the association of AID expression and IGVH mutational status is considered controversial (Leuenberger et al, 2010).…”

“…In addition, in CLL and small lymphocytic lymphoma, AID expression has been associated with unfavorable clinical course and with adverse biological parameters, i.e. higher proliferation rate, deletion of ATM and TP53 (Leuenberger et al, 2010). AID expression has been considered to be predictive for CLL with unmutated IGVH status (Palacios et al, 2010).…”