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

Slotta‐Huspenina, Julia; Koch, Ina; Leval, Laurence de; Keller, Gisela; Klier, Margit; Bink, Karin; Kremer, Marcus; Raffeld, Mark; Fend, Falko; Quintanilla-Martı́nez, Leticia

doi:10.3324/haematol.2011.055715

Cited by 54 publications

(46 citation statements)

References 48 publications

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“…These mechanisms include secondary chromosomal rearrangement at 3′ of the CCND1 locus or mutations in the 3′ untranslated region (3′UTR) that lead to the expression of truncated cyclin D1 transcripts missing part of the 3′UTR (3,4). These shorter transcripts, depleted of the destabilizing AU-rich elements and the binding sites for different microRNAs, have an extended half-life resulting in higher cyclin D1 protein levels and increased tumor aggressiveness (4,5). Alternatively, increased overexpression of cyclin D1 can occur in MCL following the amplification of the translocated t (11;14) allele (6).…”

Section: Initial Oncogenic Stepsmentioning

confidence: 99%

Molecular pathogenesis of mantle cell lymphoma

Jares

Colomer²,

Campo³

2012

J. Clin. Invest.

328

302

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Mantle cell lymphoma is a B cell malignancy in which constitutive dysregulation of cyclin D1 and the cell cycle, disruption of DNA damage response pathways, and activation of cell survival mechanisms contribute to oncogenesis. A small number of tumors lack cyclin D1 overexpression, suggesting that its dysregulation is always not required for tumor initiation. Some cases have hypermutated IGHV and stable karyotypes, a predominant nonnodal disease, and an indolent clinical evolution, which suggests that they may correspond to distinct subtypes of the disease. In this review, we discuss the molecular pathways that contribute to pathogenesis, and how improved understanding of these molecular mechanisms offers new perspectives for the treatment of patients. IntroductionMantle cell lymphoma (MCL) is a B cell malignancy with a broad spectrum of clinical, pathological, and biological features. The identification of the translocation event t(11;14)(q13;q32) and the resulting cyclin D1 overexpression were of paramount importance in recognizing the clinical and biological diversity of this tumor. In addition to this constitutive dysregulation of the cell cycle, other mechanisms such as DNA damage response alterations and activation of cell survival pathways are integrated to drive MCL pathogenesis (1, 2). New observations are expanding our views on the ontogeny and pathogenesis of this lymphoma. Furthermore, these new insights into MCL oncogenesis are promoting the development of new therapeutic strategies, intended to target the molecular mechanism of the disease, and opening up new clinical perspectives for optimal diagnosis and management of the patients.

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Section: Initial Oncogenic Stepsmentioning

confidence: 99%

Molecular pathogenesis of mantle cell lymphoma

Jares

Colomer²,

Campo³

2012

J. Clin. Invest.

328

302

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“…5). Tumor cell proliferation (13,14) and p53 aberrations (15,16), as well as the clinical Mantle Cell Lymphoma International Prognostic Index (MIPI; ref. 17), are strongly associated with outcome.…”

Section: Introductionmentioning

confidence: 99%

T-Cell Levels Are Prognostic in Mantle Cell Lymphoma

Nygren

Wasik

Baumgartner-Wennerholm

et al. 2014

Clinical Cancer Research

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Purpose: The purpose of this study was to investigate the impact of T-cell subsets on pathologic and clinical features including disease outcome in mantle cell lymphoma (MCL).Experimental Design: Cell populations were investigated using flow cytometry in diagnostic MCL (n ¼ 153) and reactive (n ¼ 26) lymph node biopsies. Levels of tumor cells, T cells, T-cell subsets, and the CD4:CD8 ratio were assessed and related to pathologic and clinical parameters.Results: MCL cases with diffuse and nodular histologic subtypes showed lower levels of T cells, especially CD4 þ T cells, than those with mantle zone growth pattern. Both CD3 and CD4 levels were lower in the nodular subtype than in mantle zone (P ¼ 0.007; P ¼ 0.003) and in the diffuse compared with the nodular subtype (P ¼ 0.022; P ¼ 0.015). The CD4:CD8 ratios were inversely correlated to tumor cell proliferation (P ¼ 0.003). Higher levels of CD3 þ and CD4 þ T cells and higher CD4:CD8 ratios were associated with indolent disease (P ¼ 0.043, 0.021, and 0.003 respectively). In univariate analysis, a high CD4:CD8 ratio, but not the histologic subtype, was correlated to longer overall survival (OS). In multivariate analysis, the CD4:CD8 ratio correlated with OS independently of Mantle Cell Lymphoma International Prognostic Index (MIPI) and high p53 expression (P ¼ 0.023).

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“…Moreover, the relative abundance of CCND1 mRNA truncated variant is associated with higher proliferation and poor outcome (27,31). However, the causal relationship between CCND1 and proliferation rate is not fully understood, because no direct association between Ki-67 index and CCND1 expression has been observed (32,33). Accordingly, CCND1 downregulation in MCL cell lines leads to variable results with regard to cell-cycle control, proliferation, and cell viability (34)(35)(36).…”

Section: As a Paradigm Of Cell-cycle Dysregulationmentioning

confidence: 99%

“…MCL blastoid variant is characterized by higher Ki-67 and mitotic index (MI), dismal prognosis, and abundant genetic alterations, such as chromosome 17p losses or TP53 mutations (6,23,33,(37)(38)(39)(40)(41). Thus, overexpression of p53 reflecting TP53 mutations is associated with a higher proliferation rate (33,38).…”

Section: Features Of MCL Correlating With Cell Proliferationmentioning

confidence: 99%

New Paradigms in Mantle Cell Lymphoma: Is It Time to Risk-Stratify Treatment Based on the Proliferative Signature?

Dreyling

Ferrero

Vogt

et al. 2014

Clinical Cancer Research

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The elucidation of crucial biologic pathways of cell survival and proliferation has led to the development of highly effective drugs, some of which have markedly improved mantle cell lymphoma (MCL) therapeutic opportunities in the past 10 years. Moreover, an undeniable clinical heterogeneity in treatment response and disease behavior has become apparent in this neoplasm. Thus, the need for biologic markers stratifying patients with MCL in risk classes deserving different treatment approaches has recently been fervently expressed. Among several newly discovered biomarkers, the dismal predictive value of a high proliferative signature has been broadly recognized in large studies of patients with MCL. Different techniques have been used to assess tumor cell proliferation, including mitotic index, immunostaining with Ki-67 antibody, and gene expression profiling. Ki-67 proliferative index, in particular, has been extensively investigated, and its negative impact on relapse incidence and overall survival has been validated in large prospective clinical trials. However, one important pitfall limiting its widespread use in clinical practice is the reported interobserver variability, due to the previous lack of a standardized approach for quantification among different laboratories. In the present review, we describe some of the major techniques to assess cell proliferation in MCL, focusing in particular on the Ki-67 index and its need for a standardized approach to be used in multicenter clinical trials. The value of MCL biologic prognostic scores (as MIPI-b) is discussed, along with our proposal on how to integrate these scores in the planning of future trials investigating a tailored therapeutic approach for patients with MCL.

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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

Cited by 54 publications

References 48 publications

Molecular pathogenesis of mantle cell lymphoma

Molecular pathogenesis of mantle cell lymphoma

T-Cell Levels Are Prognostic in Mantle Cell Lymphoma

New Paradigms in Mantle Cell Lymphoma: Is It Time to Risk-Stratify Treatment Based on the Proliferative Signature?

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