A Cyclin D1-Dependent Transcriptional Program Predicts Clinical Outcome in Mantle Cell Lymphoma

Purpose: Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation leading to cydin 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 = 53) and lymphoid tissues (n = 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 = 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 cellcycle 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 cydin D1 overexpression. Conclusions: We identified a cyclin D1-dependent transcriptional program that is overexpressed in MCL and predicts clinical outcome.

Automated summary

This study identified a cyclin D1-dependent transcriptional program that is overexpressed in MCL and predicts clinical outcome. The gene program mainly involves cell-cycle control and is directly proportional to cyclin D1 levels in MCL tumors. High expression of this program confers an adverse prognosis with shorter overall survival of the patients.