Mantle cell lymphoma (MCL) is a comparatively rare non-Hodgkin's lymphoma characterised by overexpression of cyclin D1. Many patients present with or progress to advanced stage disease within 3 years. MCL is considered an incurable disease with median survival between 3 and 4 years. We have investigated the role(s) of CCN1 (CYR61) and cell cycle regulators in progressive MCL. We have used the human MCL cell lines REC1 < G519 < JVM2 as a model for disease aggression. The magnitude of CCN1 expression in human MCL cells is REC1 > G519 > JVM2 cells by RQ-PCR, depicting a decrease in CCN1 expression with disease progression. Investigation of CCN1 isoform expression by western blotting showed that whilst expression of full-length CCN1 was barely altered in the cell lines, expression of truncated forms (18-20 and 28-30 kDa) decreased with disease progression. We have then demonstrated that cyclin D1 and cyclin dependent kinase inhibitors (p21 CIP1 and p27 KIP1) are also involved in disease progression. Cyclin D1 was highly expressed in REC1 cells (OD: 1.0), reduced to one fifth in G519 cells (OD: 0.2) and not detected by western blotting in JVM2 cells. p27 KIP1 followed a similar profile of expression as cyclin D1. Conversely, p21 CIP1 was absent in the REC1 cells and showed increasing expression in G519 and JVM2 cells. Subcellular localization detected p21 CIP1 / p27 KIP1 primarily within the cytoplasm and absent from the nucleus, consistent with altered roles in treatment resistance. Dysregulation of the CCN1 truncated forms are associated with MCL progression. In conjunction with reduced expression of cyclin D1 and increased expression of p21, this molecular signature may depict aggressive disease and treatment resistance.