Paradoxical expression of INK4c in proliferative multiple myeloma tumors: bi-allelic deletion vs increased expression

Dib, Amel; Peterson, Timothy R.; Raducha-Grace, Laura; Zingone, Adriana; Zhan, Fenghuang; Hanamura, Ichiro; Barlogie, Bart; Shaughnessy, John D.; Kuehl, W. Michael

doi:10.1186/1747-1028-1-23

Cited by 37 publications

(15 citation statements)

References 43 publications

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“…p16 INK4a was not detected in any of the HMCLs, consistent with its high degree of silencing via deletion/hypermethylation (Drexler, 1998; Tasaka et al , 1998). p18 INK4C was expressed in about half the HMCLs, consistent with previous analyses (Dib et al , 2006), while p27 Kip1 was expressed in all HMCLs except for KMS28‐BM/PE. Thus, expression of D‐type cyclins and related the cell cycle regulatory proteins in HMCLs is heterogeneous.…”

Section: Resultssupporting

confidence: 90%

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

et al. 2007

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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.

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Section: Resultssupporting

confidence: 90%

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

et al. 2007

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“…Overall, the incidence of 1p loss and 1q gain was ∼40 and 50%, respectively, which is only slightly higher than that reported in MM by us and several other groups [7, 10, 12, 26]. Notably, SNP‐array analysis pointed out the involvement of specific loci such as the CDKN2C loss at 1p and the CKS1B gain at 1q, which have been strongly suggested as putative targets in MM [21, 27–31], although in our dataset a slight correlation ( P ‐value=0.04) between DNA CN and the expression levels has been found only for CKS1B (data not shown). Chromosome 16q has been shown to be one of the most involved regions in MM.…”

Section: Discussioncontrasting

confidence: 70%

Liver disease induced by radioembolization of liver tumors

Sangro

Gil-Alzugaray

Rodríguez

et al. 2008

Cancer

339

243

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Primary plasma cell leukemia (pPCL) is a rare, yet aggressive form of de novo plasma cell tumor, distinct from secondary PCL (sPCL) which represents a leukemic transformation of pre‐existing multiple myeloma (MM). Herein, we performed a comprehensive molecular analysis of a prospective series of pPCLs by means of FISH, single nucleotide polymorphism (SNP) array and gene expression profiling (GEP). IGH@ translocations were identified in 87% of pPCL cases, with prevalence of t(11;14) (40%) and t(14;16) (30.5%), whereas the most frequent numerical alterations involved 1p (38%), 1q (48%), 6q (29%), 8p (42%), 13q (74%), 14q (71%), 16q (53%), and 17p (35%). We identified a minimal biallelic deletion (1.5 Mb) in 8p21.2 encompassing the PPP2R2A gene, belonging to a family of putative tumor suppressors and found to be significantly down‐regulated in deleted cases. Mutations of TP53 were identified in four cases, all but one associated with a monoallelic deletion of the gene, whereas activating mutations of the BRAF oncogene occurred in one case and were absent in N‐ and K‐RAS. To evaluate the influence of allelic imbalances in transcriptional expression we performed an integrated genomic analysis with GEP data, showing a significant dosage effect of genes involved in transcription, translation, methyltransferase activity, apoptosis as well as Wnt and NF‐kB signaling pathways. Overall, we provide a compendium of genomic alterations in a prospective series of pPCLs which may contribute to improve our understanding of the pathogenesis of this aggressive form of plasma cell dyscrasia and the mechanisms of tumor progression in MM. Am. J. Hematol. 2013. © 2012 Wiley Periodicals, Inc.

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“…The heterozygous deletion involved the FAF1 and CDKN2C genes, while the HD encompassed only CDKN2C. CDKN2C is a negative regulator of the G1/S cell cycle transition checkpoint and deletions of this gene have been previously identified in MM cell lines as well as in a limited number of patients (Tasaka et al, 1997;Dib et al, 2006).…”

Section: Discussionmentioning

confidence: 98%

Frequent upregulation of MYC in plasma cell leukemia

Chiecchio

Dagrada

White

et al. 2009

Genes Chromosomes & Cancer

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Plasma cell leukemia (PCL) is a rare form of monoclonal gammopathy, which can originate de novo or evolve from multiple myeloma (MM) as a terminal leukemic phase. Previous cytogenetic studies of PCL have reported the presence of complex karyotypes with involvement of multiple unidentified chromosomal regions. We report here the analysis of 12 PCL (10 primary and two secondary) by metaphase and FISH analysis combined with oligonucleotide array data (244 k, Agilent). Interphase-FISH results were compared with those from a series of 861 newly diagnosed patients with MM. Cytogenetic analysis was successful on 11 patients, all of whom showed clonal chromosomal abnormalities. Compared with MM, t(11;14)(q13;q32) (42% versus 15%; P = 0.027) and t(14;16)(q32;q23) (25% versus 4%; P = 0.010) were more frequent in PCL, although neither the specific partner chromosome involved in the IgH translocation nor the ploidy status predicted for survival. Chromosomes 1, 8, 13, and 16 showed the highest number of copy number alterations with 8q24 being the chromosomal region most frequently involved. In eight of 12 patients we found abnormalities (translocations, one amplification, small deletions, and duplications) that directly targeted or were very close to MYC. Only four of these changes were detected by routine FISH analysis using commercial probes with the others exclusively detected by arrays. Quantitative reverse transcription polymerase chain reaction demonstrated that these different abnormalities were associated with increased levels of MYC mRNA. We conclude that MYC dysregulation by complex mechanisms is one of the major molecular events in the oncogenesis of PCL.

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Paradoxical expression of INK4c in proliferative multiple myeloma tumors: bi-allelic deletion vs increased expression

Cited by 37 publications

References 43 publications

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

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

Liver disease induced by radioembolization of liver tumors

Frequent upregulation of MYC in plasma cell leukemia

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