Alterations of the cyclin D1/pRb/p16INK4A pathway in multiple myeloma

Krämer, Alwin; Schultheis, Beate; Bergmann, Jean‐François; Willer, Andreas; Hegenbart, Ute; Ho, A. D.; Goldschmidt, Hartmut; Hehlmann, R

doi:10.1038/sj.leu.2402609

Cited by 56 publications

(30 citation statements)

References 46 publications

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“…Previous reports have already shown that hypermethylation of p16 is a common phenomenon in MM and MGUS. [6][7][8][9]35 While two studies found a correlation of aberrant p16 methylation with a poorer outcome, 8,9 Guillerm Figure 1 Representative MSP analysis of patient samples. Lanes U: amplified products with primers recognizing the unmethylated gene sequence.…”

Section: Discussionmentioning

confidence: 99%

“…This epigenetic event acts as an alternative to mutations and deletions to disrupt tumor suppressor gene function. 4,5 It was reported previously that hypermethylation of the cell cycle inhibitors p15 and p16, [6][7][8][9] the apoptosis regulator DAP kinase 10 and the tumor suppressor RASSF1A 11 may occur in MM patients. Additionally, we have recently identified hypermethylation-associated silencing of the suppressor of cytokine signaling-1 (SOCS-1) gene to be a frequent epigenetic aberration in MM.…”

Section: Introductionmentioning

confidence: 99%

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DNA methylation changes in multiple myeloma

et al. 2004

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Using a candidate gene approach, we analyzed the methylation status of the promoter-associated CpG islands of 11 wellcharacterized tumor suppressor genes by methylation-specific polymerase chain reaction in five multiple myeloma (MM) cell lines and 56 patients with malignant plasma cell disorders. The frequency of aberrant methylation among the patient samples was 46.4% for SOCS-1, 35.7% for p16, 21.4% for E-cadherin, 12.5% for DAP kinase and p73, 1.8% for p15, MGMT as well as RARb, and 0% for TIMP-3, RASSF1A and hMLH1. We found at least one hypermethylated gene in 80.4% of the primary patient samples, while 33.9% harbored two or more hypermethylated genes. For the first time, we show that p73 may be hypermethylated in MM and thus be involved in the pathogenesis of plasma cell disorders. Hypermethylation of p16 at diagnosis was associated with a poorer prognosis. In patients with plasma cell leukemia, we found frequent simultaneous hypermethylation of p16, E-cadherin and DAP kinase. We conclude that aberrant methylation of tumor suppressor genes is a common event in malignant plasma cell disorders and that there is a correlation between methylation patterns and clinical characteristics in MM patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DNA methylation changes in multiple myeloma

et al. 2004

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“…[6][7][8] Information on CNAs in myeloma samples have been reported using karyotyping, fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH), and SNP-based arrays. 6,[8][9][10][11][12][13] However, to date there have been no detailed reports of CNAs in myeloma. Here we describe and annotate the major CNAs found in a large series of myeloma samples.…”

Section: Introductionmentioning

confidence: 99%

A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value

Walker

Leone

Chiecchio

et al. 2010

Blood

327

320

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To obtain a comprehensive genomic profile of presenting multiple myeloma cases we performed high-resolution single nucleotide polymorphism mapping array analysis in 114 samples alongside 258 samples analyzed by U133 Plus 2.0 expression array (Affymetrix). We examined DNA copy number alterations and loss of heterozygosity (LOH) to define the spectrum of minimally deleted regions in which relevant genes of interest can be found. The most frequent deletions are located at 1p (30%), 6q (33%), 8p (25%), 12p (15%), 13q (59%), 14q (39%), 16q (35%), 17p (7%), 20 (12%), and 22 (18%). In addition, copy number-neutral LOH, or uniparental disomy, was also prevalent on 1q (8%), 16q (9%), and X (20%), and was associated with regions of gain and loss. Based on fluorescence in situ hybridization and expression quartile analysis, genes of prognostic importance were found to be located at 1p (FAF1, CDKN2C), 1q (ANP32E), and 17p (TP53). In addition, we identified common homozygously deleted genes that have functions relevant to myeloma biology. Taken together, these analyses indicate that the crucial pathways in myeloma pathogenesis include the nuclear factor-B pathway, apoptosis, cell-cycle regulation, Wnt signaling, and histone modifications. This study was registered at http://isrctn.org as ISRCTN68454111. (Blood. 2010;116(15): e56-e65)

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“…This suggests that cyclin D1 and pRb/p105 aberrations seem to occur as alternative events in plasma cell malignancies and contribute to clinical course and prognosis. In contrast, although p16 hypermethylation is frequent, inactivation of p16 seems not to be involved in the pathogenesis of plasma cell disorders (Kramer et al, 2002).…”

Section: Other Haematopoietic and Lymphoid Malignanciesmentioning

confidence: 86%

Retinoblastoma gene family expression in lymphoid tissues

2006

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It appears more and more clear that retinoblastoma (RB) family of proteins represents key molecules in tumour suppression. This family consists of pRb/p105, p107 and pRb2/p130, which participate in a gene regulatory network that governs the cellular response to antimitogenic signals, and whose deregulation constitutes one of the hallmarks of cancer. Irrespective of their structural and biochemical similarities, RB proteins carry out different functional tasks. The expression of RB gene family in the reactive lymphoid tissues again confirms the different role of each member in cell cycle control and differentiation of normal cells. These different functional properties appear to be maintained in tumours lymphoid tissues, where alterations of the RB/p105 gene appear to be relatively rare. In this review, we will summarize the current knowledge about the role of the RB proteins in reactive and neoplastic lymphoid tissue.

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Alterations of the cyclin D1/pRb/p16INK4A pathway in multiple myeloma

Cited by 56 publications

References 46 publications

DNA methylation changes in multiple myeloma

DNA methylation changes in multiple myeloma

A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value

Retinoblastoma gene family expression in lymphoid tissues

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