@article{3ccfa1162d254738b8d3e06799dd6766,
title = "A cyclin D1-dependent transcriptional program predicts clinical outcome in mantle cell lymphoma",
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.",
author = "Santiago Demajo and Robert Albero and Guillem Clot and Giancarlo Castellano and Alba Navarro and Cristina Capdevila and Anna Enjuanes and Ferran Nadeu and Eva Gine and Magda Pinyol and Jaffe, {Elaine S.} and German Ott and Staudt, {Louis M.} and Andreas Rosenwald and Scott, {David W.} and Rimsza, {Lisa M.} and Armando Lopez-Guillermo and S{\'i}lvia Bea and Elias Campo and Pedro Jares",
note = "Funding Information: E. Gin{\'e}reports grants and nonfinancial support from Janssen; personal fees and nonfinancial support from Gilead; and grants from Roche outside the submitted work. D.W. Scott reports grants from NanoString Technologies and Roche; personal fees from AbbVie, AstraZeneca, and Celgene; and grants and personal fees from Janssen outside the submitted work. In addition, D.W. Scott has a patent for molecular subtyping of lymphoma including mantle cell lymphoma pending and licensed to NanoString. L.M. Rimsza reports a patent related to NanoString technology that has been issued and licensed. A. L{\'o}pez-Guillermo reports grants and other from Roche, Gilead/Kite, and Celgene, and other from Novartis during the conduct of the study. E. Campo reports grants from NIH, Spanish Ministerio de Ciencia, Innovaci{\'o}n y Universidades, and Generalitat de Catalunya Suport Grups de Recerca AGAUR during the conduct of the study; in addition, E. Campo has a patent for NanoString Technologies licensed. P. Jares reports grants from Instituto de Salud Carlos III-Fondo de Investigaciones Sanitarias during the conduct of the study. No disclosures were reported by the other authors. Funding Information: This study was supported by Fondo de Investigaciones Sanitarias-Instituto de Salud Carlos III (grant PI14/00355 and grant PI19/01838, to P. Jares); NIH “Molecular Diagnosis, Prognosis, and Therapeutic Targets in Mantle Cell Lymphoma” (grant P01CA229100, to E. Campo); the Spanish Ministerio de Ciencia, Innovaci{\'o}n y Universidades (grant RTI2018–094274-B-I00, to E. Campo); Generalitat de Catalu-nya Suport Grups de Recerca AGAUR (grant 2017-SGR-1142, to E. Campo); FEDER: European Regional Development Fund “Una manera de hacer Europa”; and CERCA Programme/Generalitat de Catalunya. S. Demajo was supported by a Juan de la Cierva fellowship (Spanish Ministerio de Econom{\'i}a y Competitividad). R. Albero was supported by a grant from the Leukemia and Lymphoma Society. E. Campo is an academia researcher of the Instituci{\'o} Catalana de Recerca i Estudis Avanc¸ats (ICREA) of the Generalitat de Catalunya. This work was mainly developed at the Centre Esther Koplowitz (CEK), Barcelona, Spain. The authors thank the Hematopathology Collection registered at the Biobank of Hospital Cl{\'i}nic—IDIBAPS for sample procurement. They are indebted to the Genomics core facility of the IDIBAPS and the Genomics Unit of the CRG for technical help. They are grateful to N. Agell for providing reagents and N. Garcia and S. Ruiz for their technical and logistic assistance. Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2021",
month = jan,
day = "1",
doi = "10.1158/1078-0432.CCR-20-2868",
language = "English (US)",
volume = "27",
pages = "213--225",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "1",
}