Mantle cell lymphoma cells express predominantly cyclin D1a isoform and are highly sensitive to selective inhibition of CDK4 kinase activity

Marzec, Michał; Kasprzycka, Monika; Lai, Raymond; Gladden, Andrew B.; Włodarski, Paweł; Tomczak, Ewa; Nowell̀, Peter C.; DePrimo, Samuel E.; Sadis, Seth; Eck, Stephen L.; Schuster, Stephen J.; Diehl, J. Alan; Wasik, Mariusz A.

doi:10.1182/blood-2006-04-016634

Cited by 134 publications

(104 citation statements)

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“…These negative results are in line with more recent findings by several groups, which also failed to identify a major role for the CyD1b transcript or the splice site polymorphism in MCL. [43][44][45][46] Irrespective of the reasons for the predominance of the D3'UTR transcript, the initial finding of a correlation with high total CyD1 levels, high proliferation index and shorter survival induced us to investigate the interplay between this and other known factors of poor prognosis in more detail, given the paucity of comparative data. 47 Of note, Rosenwald et al did not correlate their findings with conventional assessment of MIB1/Ki67 staining.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O N © F E R R A mentioning

confidence: 99%

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

et al. 2012

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BackgroundMantle cell lymphoma is a clinically heterogeneous disease characterized by overexpression of cyclin D1 protein. Blastoid morphology, high proliferation, and secondary genetic aberrations are markers of aggressive behavior. Expression profiling of mantle cell lymphoma revealed that predominance of the 3'UTR-deficient, short cyclin D1 mRNA isoform was associated with high cyclin D1 levels, a high "proliferation signature" and poor prognosis. Design and MethodsSixty-two cases of mantle cell lymphoma were analyzed for cyclin D1 mRNA isoforms and total cyclin D1 levels by real-time reverse transcriptase polymerase chain reaction, and TP53 alterations were assessed by immunohistochemistry and molecular analysis. Results were correlated with proliferation index and clinical outcome. ResultsPredominance of the short cyclin D1 mRNA was found in 14 (23%) samples, including four with complete loss of the standard transcript. TP53 alterations were found in 15 (24%) cases. Predominance of 3'UTR-deficient mRNA was significantly associated with high cyclin D1 mRNA levels (P=0.009) and more commonly found in blastoid mantle cell lymphoma (5/11, P=0.060) and cases with a proliferation index of >20% (P=0.026). Both blastoid morphology (11/11, P<0.001) and TP53 alterations (15/15, P<0.001) were significantly correlated with a high proliferation index. A proliferation index of 10% was determined to be a significant threshold for survival in multivariate analysis (P=0.01). ConclusionsTP53 alterations are strongly associated with a high proliferation index and aggressive behavior in mantle cell lymphoma. Predominance of the 3'UTR-deficient transcript correlates with higher cyclin D1 levels and may be a secondary contributing factor to high proliferation, but failed to reach prognostic significance in this study. Haematologica 2012;97(9):1422-1430. doi:10.3324/haematol.2011 This is an open-access paper.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 © F e r r a t a S t o r t i F o u n d a t i o n © F e r r a t a S t o r t i F o u n d a t i o n

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Section: © F E R R a T A S T O R T I F O U N D A T I O N © F E R R A mentioning

confidence: 99%

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

et al. 2012

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“…In low micromolar concentrations in in vitro and xenograft models, it inhibited a panel of Rb-positive solid tumour cell lines 76,77 . The drug was also tested in vitro against mantle cell lymphoma (mcl) 78 . Translocationmediated constitutive expression of cyclin D, the partner of cdk4 and -6, is typical of mcl.…”

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confidence: 99%

Development of Cell-Cycle Inhibitors for Cancer Therapy

Dickson¹,

Schwartz

2009

Current Oncology

197

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Modulation of the cell cycle also contributes to chemotherapy resistance. The cyclin-dependent kinases (cdks), the essential engines of the cell cycle, are therefore rational therapeutic targets. Over the last several years, a new class of anticancer therapy has been developed and extensively tested: inhibitors of cdks.These drugs have been tested as single agents with modest results. However, in combination with traditional cytotoxic chemotherapy, they have the potential to overcome drug resistance and to improve cytotoxic efficacy. THE CELL CYCLE AND ITS REGULATIONThe cell cycle governs the transition from quiescence (G0) to proliferation while ensuring the fidelity of the genetic transcript. The phases associated with dna synthesis (S phase) and mitosis (M phase) are separated by the gaps G1 and G2. The cdks join with regulatory proteins called cyclins to drive the cell through the cycle.Inhibitory proteins [cdk inhibitors (cdkis)] block specific interactions. The Ink4 (inhibitor of cdk4) class of cdkis (p16 Ink4a , p15 Ink4b , p18 Ink4c , and p19 Ink4 ) bind and inhibit cyclin D-associated kinases (cdk2, -4, and -6), and the kinase inhibitor protein (Kip) group of cdkis (p21 Waf1 , p27 Kip1 , and p57 Kip2 ) block the cyclin E/cdk2 and cyclin A/cdk2 complexes 1 .The pattern of cyclin expression defines the cell's progression through the cycle 2,3 . At least 9 cdks (cdk1-cdk9) and many cyclins (cyclin A-cyclin T) are known. The cdk /cyclin complexes are activated by specific phosphorylation of the cdk by cdk7/cyclin H, also called cdk-activating kinase 4 . Specific complexes regulate each step of the cycle. Cyclins D1-D3/cdk2, -4, and -6 drive progression through G1; cyclin E/cdk2 controls entry into S phase; cyclin A/cdk2 controls S-phase progression; cyclin A/ cdk1 (also known as cdc2) controls G2; and cdk1/ cyclin B facilitates mitosis.Entry into the cell cycle (G1) is governed by the restriction point, beyond which progression through the cycle is independent of stimuli such as ABSTRACTThe cell cycle governs the transition from quiescence through cell growth to proliferation. The key parts of the cell cycle machinery are the cyclin-dependent kinases (cdks) and the regulatory proteins called cyclins. The cdks are rational targets for cancer therapy because their expression in cancer cells is often aberrant and their inhibition can induce cell death. Inhibitors of cdks can also block transcription.Several drugs targeting the cell cycle have entered clinical trials. These agents include flavopiridol, indisulam, AZD5438, SNS-032, bryostatin-1, seliciclib, PD 0332991, and SCH 727965. Phase i studies have demonstrated that these drugs can generally be administered safely. Phase ii studies have shown little single-agent activity in solid tumors, but combination studies with cytotoxic chemotherapy have been more promising. In hematologic malignancies, reports have shown encouraging single-agent and combination activity. Pharmacodynamic studies show that the dose and schedule of these drugs are crucial to permit ma...

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“…The cyclin D1a protein isoform plays a critical role in promoting the G 1 -S transition of the cell cycle in many cell types (14). Although the expression of the D1b protein has been described in few cell types and was found to be low when compared with D1a, transfection experiments showed that it is more oncogenic than D1a (16)(17)(18)(19)(20)(21).…”

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Alteration of cyclin D1 transcript elongation by a mutated transcription factor up-regulates the oncogenic D1b splice isoform in cancer

Sanchez

Bittencourt

Laud

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

110

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Pre-mRNA splicing and polyadenylation are tightly connected to transcription, and transcriptional stimuli and elongation dynamics can affect mRNA maturation. However, whether this regulatory mechanism has a physio/pathological impact is not known. In cancer, where splice variant expression is often deregulated, many mutated oncogenes are transcriptional regulators. In particular, the Ewing sarcoma (EwSa) oncogene, resulting from a fusion of the EWS and FLI1 genes, encodes a well characterized transcription factor. EWS-FLI1 directly stimulates transcription of the CCND1 protooncogene encoding cyclin D1a and a less abundant but more oncogenic splice isoform, D1b. We show that, although both EWS and EWS-FLI1 enhance cyclin D1 gene expression, they regulate the D1b/D1a transcript ratio in an opposite manner. Detailed analyses of RNA polymerase dynamics along the gene and of the effects of an inhibitor of elongation show that EWS-FLI1 favors D1b isoform expression by decreasing the elongation rate, whereas EWS has opposite effects. As a result, the D1b/D1a ratio is elevated in EwSa cell lines and tumors. The endogenous D1b protein is enriched in nuclei, where the oncogenic activity of cyclin D1 is known to occur, and depleting D1b in addition to D1a results in a stronger reduction of EwSa cell growth than depleting D1a only. These data show that elevated expression of a splice isoform in cancer can be due to an alteration of the transcription process by a mutated transcriptional regulator and provide evidence for a physio/pathological impact of the coupling between transcription and mRNA maturation.coregulator ͉ Ewing sarcoma ͉ EWS-FLI1 ͉ polyadenylation ͉ splicing G ene expression in cancer cells is altered at the transcriptional level by many mutated oncogenes acting as transcriptional regulators. A second level of gene expression that is often altered in cancer cells is pre-mRNA splicing. Indeed, most human genes give rise to several transcripts with different exon content because of alternative splicing and alternative cleavage/ polyadenylation sites (1). Genes involved in major cellular programs often give rise to splice isoforms with distinct biological activities and deregulated expression in cancer (2, 3). In some cases, cancer-associated deregulation of alternative splicing arises from mutations within splicing regulatory sequences or from alterations of the expression of splicing factors involved in splicing regulation (2, 3). However, only few splicing factors have been found to be altered in cancer. Moreover, the role of another level of splicing regulation that involves transcriptional regulators has not been investigated yet.It is now widely accepted that pre-mRNA splicing and 3Ј-end maturation are tightly connected to transcription in Metazoans and that transcription impacts RNA processing (4, 5). It has been shown that the recruitment of processing factors and the maturation of pre-mRNAs occur at least in part cotranscriptionally and are enhanced by RNA polymerase II (Pol II) and its phosphorylation (...

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Mantle cell lymphoma cells express predominantly cyclin D1a isoform and are highly sensitive to selective inhibition of CDK4 kinase activity

Cited by 134 publications

References 25 publications

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

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

Development of Cell-Cycle Inhibitors for Cancer Therapy

Alteration of cyclin D1 transcript elongation by a mutated transcription factor up-regulates the oncogenic D1b splice isoform in cancer

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