Salt-inducible kinases in normal B-cell differentiation and malignancy

The generation of antibody-secreting plasma cells is a step-wise process involving initial B-cell activation and expansion, followed by the persistence of end-stage effector cells that reside in supportive niches. The transition through these stages requires reprogramming for high levels of secretion and adaptation to the bioenergetic demands of immunoglobulin production. To gain insight into the pathways involved, gene co-expression network analysis was applied to temporal data derived from in vitro differentiating human plasma cells. Salt-inducible kinase 1 (SIK1) was identified as a highly connected transcriptional regulator involved in the transition from a cycling plasmablast to a quiescent plasma cell. The SIK subfamily consists of three isoforms; SIK1, SIK2 and SIK3 and belongs to the AMPK-related kinase family. The family has previously been linked to the control of metabolism, in part through controlling dynamic changes in phosphorylation and subcellular localisation of cyclic adenosine monophosphate (cAMP)-regulated transcriptional co-activators (CRTCs) and class II histone deacetylates (HDACs). To assess the contribution of SIK family kinases during plasma cell differentiation, small molecule SIK inhibitors were utilised. Treatment of primary human B-cells that have activated plasma cell differentiation with the SIK inhibitors lead to a profound reduction in cell viability and these effects were also replicated in a subset of multiple myeloma cell lines. Furthermore, mice with catalytically inactive SIKs demonstrated a decrease in splenic plasma cells at steady state/following in vitro B-cell differentiation and immunisation resulted in alterations in immunoglobulin secretion. Downstream analysis of protein revealed a loss of total class II histone de-acetylase (HDAC) expression in plasmablasts (PBs) and plasma cells (PCs), but not activated B-cells indicative of different downstream mechanisms. Finally, gene expression profiling in PBs and PCs highlighted dramatic changes in genes related to phosphoinositide 3-Kinase (PI3K) signalling, glycolysis and endocytosis indicating profound metabolic collapse. These novel findings propose that the SIKs play a central, yet complex role in the development and survival of plasma cells through regulating many aspects of differentiation such as growth, proliferation, class switch recombination and glycolysis. Overall, it is reasonable to conclude that plasma cells depend on SIKs for adaptive metabolic programming, thus providing a promising target in the treatment of multiple myeloma which generate extra metabolic requirements to support growth, proliferation and immunoglobulin production.