BM mesenchymal stromal cells (BM-MSCs IntroductionThe BM microenvironment plays a crucial role in multiple myeloma (MM) pathogenesis by supporting plasma cell growth, survival, and drug resistance, which has been partially attributed to the ability of MM BM mesenchymal stromal cells (BM-MSCs) to secrete growth factors and cytokines such as IL-6, IGF-1, VEGF, and many others (1-3). These observations are indicative of paracrine growth circuits between BM-MSCs and clonal plasma cells and vice versa, which suggests that the BM niche provides an optimal substrate for MM cell localization and growth. Nevertheless, little is known about the putative mechanisms by which the BM microenvironment can lead to initiation or progression of oncogenesis in this disease.It was recently reported that cell-cell communication is mediated by exosomes. Exosomes are small nanometer-sized (50-100 nm) vesicles of endocytic origin that are released in the extracellular milieu by several cell types (4-11) under physiological and pathological conditions, including antigen presentation, transmission of infectious agents, and tumors (12, 13). The role of exosomes in tumor progression is due to the ability of tumor cell-derived exosomes to modulate and mold the host microenvironment, thereby promoting tumor cell growth and disease progression (14-17).

Monoclonal gammopathy of undetermined significance (MGUS) is

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Histone deacetylase (HDAC) inhibitors are emerging as a promising new treatment strategy in hematologic malignancies. Here we show that NVP-LAQ824, a novel hydroxamic acid derivative, induces apoptosis at physiologically achievable concentrations (median inhibitory concentration [IC50] of 100 nM at 24 hours) in multiple myeloma (MM) cell lines resistant to conventional therapies. MM.1S myeloma cell proliferation was also inhibited when cocultured with bone marrow stromal cells, demonstrating ability to overcome the stimulatory effects of the bone marrow microenvironment. Importantly, NVP-LAQ824 also inhibited patient MM cell growth in a dose- and time-dependent manner. NVP-LAQ824-induced apoptotic signaling includes up-regulation of p21, caspase cascade activation, and poly (adenosine diphosphate [ADP]) ribose (PARP) cleavage. Apoptosis was confirmed with cell cycle analysis and annexin-propidium iodide staining. Interestingly, treatment of MM cells with NVPLAQ824 also led to proteasome inhibition, as determined by reduced proteasome chymotrypsin-like activity and increased levels of cellular polyubiquitin conjugates. Finally, a study using NVP-LAQ824 in a preclinical murine myeloma model provides in vivo relevance to our in vitro studies. Taken together, these findings provide the framework for NVP-LAQ824 as a novel therapeutic in MM.

Our previous studies have shown that activation of a related adhesion focal tyrosine kinase (RAFTK) (also known as Pyk2) is required for dexamethasone (Dex)-induced apoptosis in multiple myeloma (MM) cells and that human interleukin-6 (IL-6), a known growth and survival factor for MM cells, blocks both RAFTK activation and apoptosis induced by Dex. However, the mechanism whereby IL-6 inhibits Dex-induced apoptosis is undefined. In this study, we demonstrate that protein-tyrosine phosphatase SHP2 mediates this protective effect. We show that IL-6 triggers selective activation of SHP2 and its association with RAFTK in Dex-treated MM cells. SHP2 interacts with RAFTK through a region other than its Src homology 2 domains. We demonstrate that RAFTK is a direct substrate of SHP2 both in vitro and in vivo, and that Tyr(906) in the C-terminal domain of RAFTK mediates its interaction with SHP2. Moreover, overexpression of dominant negative SHP2 blocked the protective effect of IL-6 against Dex-induced apoptosis. These findings demonstrate that SHP2 mediates the anti-apoptotic effect of IL-6 and suggest SHP2 as a novel therapeutic target in MM.