Widespread Deregulation of Phosphorylation-Based Signaling Pathways in Multiple Myeloma Cells: Opportunities for Therapeutic Intervention

Gwenny Manel Fuhler,Sander Henricus Diks,Maikel Petrus Peppelenbosch,William Garrow Kerr

doi:10.2119/molmed.2011.00013

Abstract

Multiple myeloma (MM) is a neoplasm of plasma cell origin that is largely confined to the bone marrow (BM). Chromosomal translocations and other genetic events are known to contribute to deregulation of signaling pathways that lead to transformation of plasma cells and progression to malignancy. However, the tumor stroma may also provide trophic support and enhance resistance to therapy. Phosphorylation of proteins on tyrosine, serine and threonine residues plays a pivotal role in cell growth and survival. Therefore, knowing the status of phosphorylation-based signaling pathways in cells may provide key insights into how cell growth and survival is promoted in tumor cells. To provide a more comprehensive molecular analysis of signaling disruptions in MM, we conducted a kinome profile comparison of normal plasma cells and MM plasma cells as well as their surrounding cells from normal BM and diseased BM. Integrated pathway analysis of the profiles obtained reveals deregulation of multiple signaling pathways in MM cells but also in surrounding bone marrow blood cells compared to their normal counterparts. The deregulated kinase activities identified herein, which include the mTOR (mammalian target of rapamycin)/p70S6K and ERK1/2 (extracellular signal-regulated kinases 1 and 2) pathways, are potential novel molecular targets in this lethal disease.

Highlights

Multiple myeloma (MM) is a plasma cell (PC) neoplasm that leads to renal failure, hypercalcemia and skeletal destruction resulting in a median length of survival at diagnosis of approximately 3–5 years [1]
We used the PepChip platform to determine which signaling pathways are deregulated in MM by directly comparing purified cell populations prepared from MM and normal bone marrow (BM) isolates
We successfully demonstrated that the phosphoproteome of MM cells is significantly different from that of their normal PC counterparts

Summary

Introduction

Multiple myeloma (MM) is a plasma cell (PC) neoplasm that leads to renal failure, hypercalcemia and skeletal destruction resulting in a median length of survival at diagnosis of approximately 3–5 years [1]. There are thought to be three general categories of factors that promote the growth and/or survival of MM cells in vivo [2,3]. The first consists of factors such as interleukin 6 (IL-6), IL-10 and interferon-α that trigger JAK/STAT (janus kinase/signal transducer and activator of transcription) pathways, which can lead to activation of mitogen-activated protein (MAP) kinases that drive cell proliferation. The third pathway involves the B-lineage–specific BAFF (B-cell activating factor) and April receptors, whose ligands can trigger activa-. Tion of PI3K/Akt and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activities that promote cell survival. Small changes in the expression profiles in this part of the transcriptome can lead to large changes in the enzymatic profile of the cell, leading to significant differences in cell functioning [7]. An if not more important, goal is to define the activity of the proteins that control the status of signal-

Methods

Results

Conclusion