Cell Cycle Dysregulation in Mantle Cell Lymphoma: Genomics and Therapy

Abstract

Cell cycle dysregulation caused by aberrant cyclin D1 and CDK4 expression is a major determinant for proliferation of cancer cells in mantle cell lymphoma (MCL). Inhibition of CDK4/6 induces G1 arrest of MCL cells in patients, appearing to deepen and prolong the clinical response to partner agents. This article reviews aberrations of cell cycle genes in MCL cells and clinical trials of CDK4/6 inhibitors for MCL. Integrative longitudinal functional genomics is discussed as a strategy to discover genomic drivers for resistance in cancer cells and cancer-immune interactions that potentially contribute to the clinical response to palbociclib combination therapy in MCL.

Keywords: CDK4; Cyclin D1; Ibrutinib; Mantle cell lymphoma; Palbociclib; Rb; p16(INK4a).

Fig. 1.

(A) A schema of the mammalian cell cycle. When released from Rb after it is phosphorylated by cyclin D1–CDK4, E2F1 directly activates the transcription of CCNA2 (encoding cyclin A), TK1 (encoding thymidine kinase), PCNA (encoding proliferating cell nuclear antigen), CDK1 (encoding cyclin-dependent kinase I), and EZH2 (encoding EZH2), among other target genes. (B) Three oral small molecule reversible CDK4/6 inhibitors.