Functional regulation of D‐type cyclins by insulin‐like growth factor‐I and serum in multiple myeloma cells

Abstract

Summary D‐type cyclin genes are universally dysregulated in multiple myeloma (MM), but the functional consequences are unclear as D‐type cyclin gene expression does not correlate with proliferation or disease progression. We examined the protein expression and regulation of D‐type cyclins and other cell cycle regulators in human myeloma cell lines and primary CD138+ plasma cells (PCs). Cyclin D1, cyclin D2, cyclin dependent kinase (CDK) 4, CDK6, p27Kip1 p18INK4C and retinoblastoma protein (pRb) were absent in normal PCs, heterogeneously expressed in primary MM cells and positively correlated with disease activity/progression. Cyclins D1 and D2 complexed with both CDK4 and CDK6, suggesting that both phosphorylate pRb in MM. Furthermore, cyclin D2 expressed via either t(14;16) or t(4;14) IgH translocations was functionally upregulated by fetal calf serum or insulin‐like growth factor‐I, leading to pRb phosphorylation and cell cycle entry/progression, and in some cases inversely correlated with p27Kip1. However, pRb phosphorylation and cell cycle progression mediated by cyclin D1 expressed via t(11;14) was less dependent on exogenous stimuli. These data suggest that the presence or absence of specific IgH translocations underlying aberrant D‐type cyclin expression may influence their response to mitogens in the bone marrow microenvironment. We showed for the first time that D‐type cyclins are functionally regulated in MM, differentially responsive to exogenous growth factors and upregulated with disease progression.

MUC1-C drives MYC in multiple myeloma

“…42 However, studies of different MM cells with (U266, NCI-H929) and without (RPMI8226, MM1.S, KMS28PE) cyclin D1 expression have indicated that sensitivity to targeting MUC1-C is not dependent on cyclin D1. 28,61 In MM cells, the upregulation of b-catenin is associated with increases in MYC expression, consistent with MYC as a downstream WNT/b-catenin target gene. 59 In addition, transcriptional profiling has shown MYC pathway activation in about two-thirds of MM patient samples, but not in MGUS, supporting a role for MYC in the pathogenesis of MM.…”

APRIL promotes cell-cycle progression in primary multiple myeloma cells: influence of D-type cyclin group and translocation status

“…In agreement with our Western blotting data and our previous results, we found CDK4 and CDK6 expression in both cyclin D1 ϩ and cyclin D2 ϩ cases. 13 Our understanding of the regulation of proliferation in primary MM cells has been hampered by the poor survival of these cells during in vitro culture. To overcome these difficulties, we adapted a culture system that used 20% pooled plasma from MM patients.…”

“…13 However, attempts to study growth and proliferation in primary MM cells have not been successful because of the great difficulty in maintaining viable malignant plasma cells in vitro. 14 Moreover, proliferative behavior may differ depending on genetic subgroup, hence leading to apparently contradictory results.…”

Inhibition of cell cycle progression by dual phosphatidylinositol-3-kinase and mTOR blockade in cyclin D2 positive multiple myeloma bearing IgH translocations

“…We recently showed, for the first time, that MM cells from patients with t(4;14) and t(14;16) respond to mitogenic growth factors with upregulation of cyclin D2, CDK4 and 6, leading to retinoblastoma protein (pRb) phosphorylation and cell cycle entry/progression, thus providing functional validation for the observed D-type cyclin dysregulation in this disease. 7, 8 In contrast, MM cells with t(11;14) disease characterized by overexpression of cyclin D1 were less dependent on exogenous stimuli for cell cycle progression.…”