ALTERATIONS OF THE CYCLIN D1 P16-PRB PATHWAY IN MANTLE CELL LYMPHOMA/

Mantle cell lymphoma (MCL) has recently become generally accepted as a subentity of malignant lymphomas that is characterized by the chromos omal translocation t(11;14)(q13;q32), resulting in the overexpression of cyclin D1, Cyclin D1 forms a complex with cell cycle-dependent kina se (cdk) 4, which inactivates the retinoblastoma protein (pRB) via pho sphorylation. However, in transgenic mice, the overexpression of cycli n D1 alone is not sufficient for the development of malignant lymphoma . To determine whether other members of the pRB pathway contribute to the malignant transformation of MCL, we analyzed 37 cases of MCL that were well characterized by morphology, immunophenotype, and/or interph ase cytogenetics [detection of t(11;14)(q13;q32)]. Interphase fluoresc ence in situ hybridization was performed using a cosmid contig (250 kb ) of the CDKN2/p16 region (encoding an inhibitor of the cyclin D1/cdk4 complex) and a phage contig (200 kb) of the Rb region, CDKN2/p16 dele tion was detected in 15 cases (41%), including 6 homozygous deletions; Rb was deleted in 15 cases (41%), all of which were hemizygous deleti ons. Nine cases (24%) had deletions of both CDKN2/p16 and Rb, Further analysis of a subset of 17 MCLs revealed a highly significant correlat ion between CDKN2/p16 deletion and proliferation index, determined by the rate of Ki67 expression (P = 0.014; t test), No significant correl ation was found between CDKN2/p16 deletion and the blastoid variant of MCL (P = 0.23; Fisher's test) or between proliferation index and blas toid morphology (P = 0.51; t test). Deletion of Rb did not have any im pact on cell proliferation in addition to CDKN2/p16 deletion (P = 0.76 ; t test), Additional analysis of 13q14 deletions suggests that these deletions may target another gene telomeric to Rb, We conclude that de letion of CDKN2/p16 occurs in approximately one-half of MCLs and is a more relevant indicator of the proliferative features as compared to m orphological criteria, In contrast, although deletions of chromosomal band 13q14 are frequent in MCL, inactivation of Rb seems not to be inv olved in the pathogenesis of MCL.