A cyclin D1-dependent transcriptional program predicts clinical outcome in mantle cell lymphoma
Demajo, Santiago (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Albero Gallego, Robert (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Clot, Guillem (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Castellano, Giancarlo (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Navarro, Alba (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Capdevila, Cristina (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Enjuanes, A. (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Nadeu, Ferran (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Giné, Eva (Hospital Clínic i Provincial de Barcelona)
Pinyol, Magda (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Jaffe, E.S. (Hematopathology Section. NCI)
Ott, German (Robert Bosch Hospital (Stuttgart, Alemanya))
Staudt, L.M. (Center for Cancer Research. Lymphoid Malignancies Branch. NCI)
Rosenwald, Andreas (Institute of Pathology. University of Wurzburg)
Scott, D.W. (Centre for Lymphoid Cancer. British Columbia Cancer Agency)
Rimsza, L.M. (Department of Pathology. Mayo Clinic)
Lopez-Guillermo, A. (Hospital Clínic i Provincial de Barcelona)
Bea, Sílvia (Centro de Investigación Biomédica en Red de Cáncer)
Campo, Elias (Hospital Clínic i Provincial de Barcelona)
Jares, Pedro (Hospital Clínic i Provincial de Barcelona)

Fecha:	2021
Resumen:	Purpose: Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation leading to cyclin D1 overexpression. Cyclin D1 is a major cell-cycle regulator and also regulates transcription, but the impact of cyclin D1-mediated transcriptional dysregulation on MCL pathogenesis remains poorly understood. The aim of this study was to define a cyclin D1-dependent gene expression program and analyze its prognostic value. Experimental Design: We integrated genome-wide expression analysis of cyclin D1-silenced and overexpressing cells with cyclin D1 chromatin-binding profiles to identify a cyclin D1-dependent transcriptional program in MCL cells. We analyzed this gene program in two MCL series of peripheral blood samples (n ¼ 53) and lymphoid tissues (n ¼ 106) to determine its biological and clinical relevance. We then obtained a simplified signature of this program and evaluated a third series of peripheral blood MCL samples (n ¼ 81) by NanoString gene expression profiling to validate our findings. Results: We identified a cyclin D1-dependent transcriptional program composed of 295 genes that were mainly involved in cell-cycle control. The cyclin D1-dependent gene program was overexpressed in MCL tumors directly proportional to cyclin D1 levels. High expression of this program conferred an adverse prognosis with significant shorter overall survival of the patients. These observations were validated in an independent cohort of patients using a simplified 37-gene cyclin D1 signature. The cyclin D1-dependent transcriptional program was also present in multiple myeloma and breast tumors with cyclin D1 overexpression. Conclusions: We identified a cyclin D1-dependent transcriptional program that is overexpressed in MCL and predicts clinical outcome.
Ayudas:	Ministerio de Economía y CompetitividadPI14/00355 Instituto de Salud Carlos III PI19/01838 Agencia Estatal de Investigación RTI2018-094274-B-I00 Generalitat de Catalunya 2017/SGR-01142
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Lengua:	Anglès
Documento:	Article ; recerca ; Versió sotmesa a revisió
Materia:	Mantle cell lymphoma ; Cyclin D1 ; Gene expression profiling
Publicado en:	Clinical cancer research, Vol. 27, Num. 1 (January 2021) , p. 213-225, ISSN 1557-3265

DOI: 10.1158/1078-0432.CCR-20-2868
PMID: 33046520

Postprint 56 p, 1.2 MB

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