CKS1B, Mapping to an Amplicon on Chromosome 1q21 and over Expressed in Aggressive Disease, Regulates Multiple Myeloma Growth and Survival through p27^Kip1-Dependent and Independent Mechanisms.

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 p27^Kip1 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 p27^Kip1 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 p27^Kip1, cell cycle arrest and apoptosis. Over expression of a non-degradable form of p27^Kip1 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 p27^Kip1-related and unrelated mechanisms.