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 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 D1dependent 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.

Ambra1 modulates the sensitivity of mantle cell lymphoma to palbociclib by regulating cyclin D1

“…Targeting the cell cycle is a rational approach for MCL therapy, as aberrant expression of cyclin D1 and dysregulation of CDK4 underlie cell cycle progression and MCL cell proliferation 32 . Cyclin D1, a major cell cycle regulator, is one of three unlinked D-type cyclin gene family members that also regulates transcription 33 , 34 . Cyclin D1 regulates the migration and invasion of MCL cells and can be viewed as a true operator in the pathogenesis of MCL 35 .…”

CDC42EP3 promotes glioma progression via regulation of CCND1

“…CCND1 (cyclin D1) is one of the regulators of CDK kinases by forming complexes with CDK4 or CDK6 as a subunit [ 19 ], whose tumor-promoting role in the development of human cancers has been intensively investigated [ 20 ]. On one hand, CCND1-dependent transcriptional program has been found to play an important role in the oncogenesis and tumor development and even could predict clinical outcome of some types of cancer such as mantle cell lymphoma [ 21 , 22 ]. On the other hand, the expression of CCND1 was also found to be commonly regulated through transcription-related pathway.…”

Targeting MYO1B impairs tumorigenesis via inhibiting the SNAI2/cyclin D1 signaling in esophageal squamous cell carcinoma

“…Previous studies illustrated that cyclin D1 acts as a transcriptional regulator via interaction with transcription factor and chromatin modifiers to modulate gene expression (Coqueret, 2002; Pestell, 2013). Moreover, emerging data have reported that cyclin D1 binds to promote regions of active genes universally, and induces a global transcriptional down‐modulation via the interaction with the transcriptional machinery in lymphoid cells (Albero et al, 2018; Demajo et al, 2020). These results implied that dysregulation of cyclin D1 in malignant cells plays an important role in cancer development.…”