A cyclin D1-dependent transcriptional program predicts clinical outcome in mantle cell lymphoma

Santiago Demajo, Robert Albero, Guillem Clot, Giancarlo Castellano, Alba Navarro, Cristina Capdevila, Anna Enjuanes, Ferran Nadeu, Eva Gine, Magda Pinyol, Elaine S. Jaffe, German Ott, Louis M. Staudt, Andreas Rosenwald, David W. Scott, Lisa M. Rimsza, Armando Lopez-Guillermo, Sílvia Bea, Elias Campo, Pedro Jares

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)213-225
Number of pages13
JournalClinical Cancer Research
Volume27
Issue number1
DOIs
StatePublished - Jan 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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