Diffuse large B-cell lymphoma cycling off the main track

Progression through the cell cycle is dependent upon cyclin-dependent kinases that phosphorylate downstream proteins involved in DNA replication and cell division. Cyclin-dependent kinases (CDKs) are activated by cyclins that function as allosteric regulatory proteins, and are inhibited by CDK inhibitors. The different checkpoints of cell cycle progression are tightly regulated by distinct types of cyclin–CDK couples that may vary according to cell differentiation [1]. Notwithstanding, the activity of cyclins is characterized by a large degree of redundancy [1]. D-type cyclins associate with CDK4 or CDK6 and are important regulators of the cell cycle G1–S transition [1]. While CDKs are stably expressed during the cell cycle, cyclins are transiently expressed. D-type cyclins are physiologically expressed following external mitogenic stimuli and their regulation is quite complex; cyclin D1 expression, for example, is regulated at the transcriptional, translational, and protein levels [2]. Not surprisingly for a crucial regulatory protein that responds to mitogenic stimuli and is involved in the G1–S cell cycle transition, cyclin D1 is overexpressed in different types of cancer and contributes thereby to oncogenesis [2]. Most typically, it is overexpressed in mantle cell lymphoma and a subset of plasma cell neoplasia. However, it is also overexpressed in carcinomas, most notably in non-small cell cancer of the lung, in breast carcinoma, and in esophageal cancer [2]. In mantle cell lymphoma (MCL) and plasma cell neoplasia, cyclin D1 is predominantly overexpressed as a consequence of increased transcription due to the translocation t(11;14)(q13;q32) bringing the coding gene (CCND1) under the regulation of the active immunoglobulin heavy chain gene locus [3]. Also, truncation of the 3′ untranslated region of cyclin D1 mRNA has been shown in a number of cases of MCL to be responsible for cyclin D1 overexpression. Truncation of the 3′ untranslated region prevents miR-16 from binding the mRNA, which is necessary for the normal down-regulation of transcript levels [4]. Inhibition of nuclear export or inhibition of proteolysis leading to increased cyclin D1 expression and activity has not been reported in lymphoma, but is a mechanism that is described in carcinomas [5]. Cyclin D1 expression is also deregulated in hairy cell leukemia and, as described in this issue of Leukemia and Lymphoma by Vela-Chavez et al., in a subgroup of diffuse large B-cell lymphoma [6]. However, cyclins D2 and D3 are the most frequently expressed D-type cyclins in DLBCL [7]. These cyclins may also be up-regulated as a consequence of genetic changes. Up-regulation of cyclin D3 expression has been described secondary to the translocation t(6;14)(p21;q32) in DLBCL, but only in a minority of cases [8]. More important, cyclin D3 may be up-regulated by amplification of its gene CCND3 located on chromosome region 6p21, a region that is frequently amplified in DLBCL [9]. The mechanism of up-regulation of cyclin D2 is not well known, but its gene CCND2 is located on chromosome region 12p13, a region that also is often gained in DLBCL [9]. Of note, both cyclin D2 and cyclin D3 expression is correlated with a worse prognosis in DLBCL [10,11]. Of interest, expression of cyclin D2 is characteristic of the activated B-cell subtype of DLBCL, which in itself is also associated with a worse prognosis [12]. Whether the expression of cyclin D1 is correlated with survival in DLBCL is not known, but cyclin D1 expression is also predominantly seen in the activated B-cell subtype of DLBCL, as reported by Vela-Chavez et al. [6]. The mechanisms contributing to cyclin D1 overexpression in a small subset of DLBCL are currently unknown. DLBCLs that overexpress cyclin D1 show no evidence of the t(11;14)(q13;q32) translocation, as described before, as well as by Vela-Chavez et al. [6]. In addition, it has not been demonstrated that amplification or gain of the CCND1 gene contributes to cyclin D1 expression in DLBCL. Future studies need to be performed to investigate whether cyclin D1 might be up-regulated in DLBCL by modification of transcript stability, interference with nuclear export, or proteolysis in the cytoplasm, as shown in some carcinomas. Alternatively, as cyclins D2 and D3 are the preferentially expressed cyclins in DLBCL and as cyclins show functional redundancy, cyclin D1 may be ‘physiologically’ up-regulated in those cases that for some, potentially genetic, reason fail to express cyclin D2 or D3. A more complete understanding of the cell cycle regulatory pathways in DLBCL is warranted to consider the use of novel therapeutic agents such as specific cyclin-dependent kinase inhibitors as part of the treatment for this disease in the future.

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