Analysis of IgVH gene mutations in B cell chronic lymphocytic leukaemia according to antigen‐driven selection identifies subgroups with different prognosis and usage of the canonical somatic hypermutation machinery

• Published in: British journal of haematology 2004-07, Vol.126 (1), p.29-42
• Main Authors: Degan, Massimo, Bomben, Riccardo, Bo, Michele Dal, Zucchetto, Antonella, Nanni, Paola, Rupolo, Maurizio, Steffan, Agostino, Attadia, Vincenza, Ballerini, Pier Ferruccio, Damiani, Daniela, Pucillo, Carlo, Poeta, Giovanni Del, Colombatti, Alfonso, Gattei, Valter
• Format: Article
• Language: English
• Subjects: antigen selection; Biological and medical sciences; chronic lymphocytic leukaemia; Hematologic and hematopoietic diseases; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; prognosis; somatic hypermutation; translesion DNA polymerases
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/j.1365-2141.2004.04985.x

Summary Cases of B‐cell chronic lymphocytic leukaemia (B‐CLL) with mutated (M) IgVH genes have a better prognosis than unmutated (UM) cases. We analysed the IgVH mutational status of B‐CLL according to the features of a canonical somatic hypermutation (SHM) process, correlating this data with survival. In a series of 141 B‐CLLs, 124 cases were examined for IgVH gene per cent mutations and skewing of replacement/silent mutations in the framework/complementarity‐determining regions as evidence of antigen‐driven selection; this identified three B‐CLL subsets: significantly mutated (sM), with evidence of antigen‐driven selection, not significantly mutated (nsM) and UM, without such evidence and IgVH gene per cent mutations above or below the 2% cut‐off. sM B‐CLL patients had longer survival within the good prognosis subgroup that had more than 2% mutations of IgVH genes. sM, nsM and UM B‐CLL were also characterized for the biased usage of IgVH families, intraclonal IgVH gene diversification, preference of mutations to target‐specific nucleotides or hotspots, and for the expression of enzymes involved in SHM (translesion DNA polymerase ζ and η and activation‐induced cytidine deaminase). These findings indicate the activation of a canonical SHM process in nsM and sM B‐CLLs and underscore the role of the antigen in defining the specific clinical and biological features of B‐CLL.