title: 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=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=0.002) and p53 deletion (P=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=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.
authors.affiliation: Department of Pathology, Institute of Surgical Pathology, University Hospital, CH-8091Zurich, Switzerland.
authors.forename: Mona
authors.initials: M
authors.lastname: Leuenberger
authors.forename: Simona
authors.initials: S
authors.lastname: Frigerio
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
authors.forename: Franziska
authors.initials: F
authors.lastname: Noetzli
authors.forename: Dimitri
authors.initials: D
authors.lastname: Korol
authors.forename: Dieter R
authors.initials: DR
authors.lastname: Zimmermann
authors.forename: Carole
authors.initials: C
authors.lastname: Gengler
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Probst-Hensch
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Marianne
authors.initials: M
authors.lastname: Tinguely
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D003564:Cytidine Deaminase / Q000096:biosynthesis*; D004252:DNA Mutational Analysis; D005260:Female; D015321:Gene Rearrangement; D005803:Genes, Immunoglobulin / Q000235:genetics; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D046888:Tissue Array Analysis; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D014408:Biomarkers, Tumor; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase