CKS1B, Mapping to an Amplicon on Chromosome 1q21 and over Expressed in Aggressive Disease, Regulates Multiple Myeloma Growth and Survival through p27Kip1-Dependent and Independent Mechanisms.

Abstract

While deregulated expression of a D-type cyclin is thought to represent an initiating event in myelomagenesis, the molecular mechanisms of disease progression are not understood. We recently reported that disease progression and high-risk disease are strongly correlated with increased copy number and expression of genes mapping to chromosome 1q. Here we report that elevated expression of CKS1B, a regulatory subunit of the SCF-Skp2 ubiquitin ligase that regulates p27Kip1 protein stability, mapping to an amplicon at 1q21 and over expressed in high-risk myeloma, is required for myeloma cell survival both in vitro and in-vivo. CKS1B expression, absent in plasma cells from healthy individuals and the benign plasma cell dyscrasia monoclonal gammopathy of undetermined significance, is inversely correlated with p27Kip1 protein levels in primary MM. Silencing of CKS1B in MM cell lines JJN3 and OCI-MY5 using shRNAs delivered by constitutive and inducible lentivirus vectors induced stabilization of p27Kip1, cell cycle arrest and apoptosis. Over expression of a non-degradable form of p27Kip1 in JJN3 and OCI-MY5 cells inhibited cell cycle progression, but did not induce apoptosis. We propose that CKS1B may play in important role in myeloma progression through p27Kip1-related and unrelated mechanisms.