DNA replication licensing in peripheral B-cell lymphoma.

Peripheral B-cell lymphomas representing 90% of lymphoid neoplasms are divided into low- and high-growth fraction lymphomas. Here we investigate regulation of DNA replication licensing during B-cell lymphomagenesis. Combined analysis of origin licensing factors Mcm2 and geminin with the proliferation marker Ki67 in SLL/CLL, MCL, DLBCL and Burkitt lymphoma reveals for the first time the precise cell cycle state of these entities. Given that tight Mcm2 downregulation defines the quiescent state (G0) and that both high- and low-growth fraction lymphomas express Mcm2, the data demonstrate that neoplastic lymphocytes of SLL/CLL and MCL reside in an "in-cycle" G1 state and not in G0 as previously thought. Absence of the S/G2/M phase marker geminin in SLL/CLL and MCL further indicates failure of cell cycle progression in these tumours. In contrast, the high-growth fraction lymphomas DLBCL and Burkitt lymphoma exhibit differential expression of geminin, with the geminin/Ki67 ratio increasing for more aggressive neoplasms in keeping with a shortened G1 phase and thus representing an important discriminator for differential diagnosis. These data provide new insights into abrogation of cell cycle control during B cell lymphomagenesis and suggest that combined analysis of origin licensing factors may contribute to improved treatment decisions and prognosis in haematopoietic malignancies.