The lymphoma-associated NPM-ALK oncogene elicits a p16INK4a/pRb-dependent tumor-suppressive pathway

Martinelli, Paola; Bonetti, Paola; Sironi, Cristina; Pruneri, Giancarlo; Fumagalli, Caterina; Raviele, Paola Rafaniello; Volorio, Sara; Pileri, Stefano; Chiarle, Roberto; McDuff, Fiona Kate Elizabeth; Tusi, Betsabeh Khoramian; Turner, Suzanne D.; Inghirami, Giorgio; Pelicci, Pier Giuseppe; Colombo, Emanuela

doi:10.1182/blood-2010-08-301135

Cited by 22 publications

(20 citation statements)

References 31 publications

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“…Our study provides evidence that the quantitative evaluation of CS markers in HRS cells of cHL can have a prognostic significance in line with, and probably grounded on, their biologic role analogously to other neoplasias (40)(41)(42).…”

Section: Discussionmentioning

confidence: 53%

Cellular Senescence Markers p16INK4a and p21CIP1/WAF Are Predictors of Hodgkin Lymphoma Outcome

Caliò

Zamò

Ponzoni

et al. 2015

Clinical Cancer Research

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Purpose: There is evidence that Hodgkin Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (cHL) could display some molecular and morphologic markers of cellular senescence (CS). We hypothesized that CS mechanisms may have potential prognostic relevance in cHL and investigated whether the expression of the well-established CS biomarkers p21 CIP1/WAF1 and p16 INK4a by HRS cells might be predictive of the probability of event-free survival (EFS).Experimental Design: The study analyzed a retrospective cohort of 147 patients and the results were validated on a cohort of 91 patients independently diagnosed and treated in a different institution. p16INK4a and p21 CIP1/WAF1 were categorized as dichotomous variables (< or ! 30% of HRS cells at diagnosis) and evaluated in univariate and multivariate analysis.Results: Both molecules were independent prognostic factors. A positive staining of one of the two molecules in more than 30% HRS cells predicted a better EFS (P < 0.01). p16INK4a /p21together as a unique categorical variable (both <30%, either <30%, both ! 30%) sorted out three prognostic groups with better, intermediate, or worse outcome either overall or within I-II, bulky and advanced stages. The presence or the lack of the robust expression of p21 CIP1/WAF1 and/or p16 INK4a defined the prognosis in our series.Conclusions: These findings point to (i) the relevance of CS-related mechanisms in cHL, and to (ii) the prognostic value of a simple, reproducible, and low-cost immunohistochemical evaluation of p16INK4a and p21 CIP1/WAF1 expression.

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Section: Discussionmentioning

confidence: 53%

Cellular Senescence Markers p16INK4a and p21CIP1/WAF Are Predictors of Hodgkin Lymphoma Outcome

Caliò

Zamò

Ponzoni

et al. 2015

Clinical Cancer Research

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“…Gene expression of two key regulators of cellular senescence, the tumor suppressor proteins, p16INKA and p14ARF, is silenced by H3K27me3 marks on the INK4a/ARF -gene locus in growing cells (Agherbi et al, 2009). Conversely, oncogenic-RAS-induced senescence leads to JMJD3 expression, which contributes to the activation of p16INK4A (Martinelli et al, 2011). Cellular senescence is also induced by the loss of the tumor repressor gene, B cell translocation gene 3 (BTG3) through increased JMJD3 expression and subsequent p16INK4A activation (Lin et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

JMJD3 as an epigenetic regulator in development and disease

Burchfield

Wang

et al. 2015

The International Journal of Biochemistry & Cell Biology

119

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Gene expression is epigenetically regulated through DNA methylation and covalent chromatin modifications, such as acetylation, phosphorylation, ubiquitination, sumoylation, and methylation of histones. Histone methylation state is dynamically regulated by different groups of histone methyltransferases and demethylases. The trimethylation of histone 3 (H3K4) at lysine 4 is usually associated with the activation of gene expression, whereas trimethylation of histone 3 at lysine 27 (H3K27) is associated with the repression of gene expression. The polycomb repressive complex contains the H3K27 methyltransferase Ezh2 and controls dimethylation and trimethylation of H3K27 (H3K27me2/3). The Jumonji domain containing-3 (Jmjd3, KDM6B) and ubiquitously transcribed X-chromosome tetratricopeptide repeat protein (UTX, KDM6A) have been identified as H3K27 demethylases that catalyze the demethylation of H3K27me2/3. The role and mechanisms of both JMJD3 and UTX have been extensively studied for their involvement in development, cell plasticity, immune system, neurodegenerative disease, and cancer. In this review, we will focus on recent progresses made on understanding JMJD3 in the regulation of gene expression in development and diseases. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease.

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“…The ALK fusion products have significant oncogenic activity. [10][11][12][13][14] Because of the expression pattern, ALK fusion products have become an enticing chemotherapeutic target. Recently, the ALK inhibitor crizotinib was shown to be an effective therapy in patients with ALK-rearranged non-small cell lung cancers.…”

mentioning

confidence: 99%

ALK alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients

et al. 2012

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The lymphoma-associated NPM-ALK oncogene elicits a p16INK4a/pRb-dependent tumor-suppressive pathway

Abstract: Oncogene-induced senescence (OIS) is

Cited by 22 publications

References 31 publications

Cellular Senescence Markers p16INK4a and p21CIP1/WAF Are Predictors of Hodgkin Lymphoma Outcome

Cellular Senescence Markers p16INK4a and p21CIP1/WAF Are Predictors of Hodgkin Lymphoma Outcome

JMJD3 as an epigenetic regulator in development and disease

ALK alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients

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