Mutually Exclusive Cyclin-Dependent Kinase 4/Cyclin D1 and Cyclin-Dependent Kinase 6/Cyclin D2 Pairing Inactivates Retinoblastoma Protein and Promotes Cell Cycle Dysregulation in Multiple Myeloma

Abstract

Multiple myeloma, the second most common hematopoietic cancer, ultimately becomes refractory to treatment when selfrenewing multiple myeloma cells begin unrestrained proliferation by unknown mechanisms. Here, we show that one, but not more than one, of the three early G 1 D cyclins is elevated in each case of multiple myeloma. Cyclin D1 or D3 expression does not vary in the clinical course, but that alone is insufficient to promote cell cycle progression unless cyclindependent kinase 4 (cdk4) is also elevated, in the absence of cdk6, to phosphorylate the retinoblastoma protein (Rb). By contrast, cyclin D2 and cdk6 are coordinately increased, thereby overriding the inhibition by cdk inhibitors p18 INK4c and p27 Kip1 and phosphorylating Rb in conjunction with the existing cdk4. Thus, cyclin D1 pairs exclusively with cdk4 and cdk6 pairs only with cyclin D2, although cyclin D2 can also pair with cdk4 in multiple myeloma cells. The basis for this novel and specific cdk/D cyclin pairing lies in differential transcriptional activation. In addition, cyclin D1-or cyclin D3-expressing multiple myeloma cells are uniformly distributed in the bone marrow, whereas cdk6-specific phosphorylation of Rb occurs in discrete foci of bone marrow multiple myeloma cells before proliferation early in the clinical course and is then heightened with proliferation and disease progression. Mutually exclusive cdk4/cyclin D1 and cdk6/ cyclin D2 pairing, therefore, is likely to be a critical determinant for cell cycle reentry and progression and may play a pivotal role in the expansion of self-renewing multiple myeloma cells. (Cancer Res 2005; 65(24): 11345-53)

Glycogen synthase kinase-3β and p38 phosphorylate cyclin D2 on Thr280 to trigger its ubiquitin/proteasome-dependent degradation in hematopoietic cells

“…The cyclin D2 expression we found in primary myeloma cells is also consistent with previous studies implicating D-type cyclins including cyclin D2 in pathogenesis of MM (Bergsagel et al, 2005;Ely et al, 2005). Importantly, we demonstrated that cyclin D2 is very labile in primary leukemic and myeloma cells and is regulated through the post-translational regulatory mechanisms that are similar to those in IL-3-dependent hematopoietic cells.…”

Antitumour and antiangiogenic effects of Aplidin® in the 5TMM syngeneic models of multiple myeloma

“…Translocation of the cyclinD1 gene to the immunoglobulin heavy-chain locus t(11;14) and overexpression of cyclin D1 RNA have been implicated in cell-cycle dysregulation in MM (Bergsagel and Kuehl, 2001). The group of Chen-Kiang, however, showed that in the transition from G1 to S phase, retinoblastoma becomes phosphorylated by the exclusive pairing of CDK4 with cyclin D1 or CDK6 with cyclin D2 (Ely et al, 2005). The decreased expression of both CDK4 and cyclin D1 by Aplidin thus explains the arrest seen in cell-cycle progression.…”

The impact of cyclin D1 mRNA isoforms, morphology and p53 in mantle cell lymphoma: p53 alterations and blastoid morphology are strong predictors of a high proliferation index

“…27 A potential explanation for this lack of correlation between CyD1 levels and proliferation in t(11;14)-positive MM was proposed by Ely et al, who demonstrated that CyD1 alone is not sufficient to induce retinoblastoma protein phosphorylation and cell cycle progression in CyD1-positive MM, unless CDK4 is also elevated. 51 Of note, average CyD1 mRNA levels in t(11;14)-positive MM are significantly higher than in MCL, probably because of the higher transcriptional activity of the translocated IgH locus in neoplastic plasma cells. 30,52 Hairy cell leukemia, another B-cell non-Hodgkin's lymphoma expressing CyD1 due to an unknown mechanism, usually has a very low proliferation index.…”