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  • Increasing evidence supports that the B


    Increasing evidence supports that the B-cell lymphoid malignancies develop from various stages of B-cells, hijacking the mechanisms that drive B-cell differentiation and activation [27]. For instance, mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) originate from the pre-germinal center (GC) mature B-cells, while most of the non-Hodgkin’s lymphomas and multiple myelomas (MMs) originate from the GC B-cells or B-cells that have gone through a germinal center reaction. Each of these B-cell lymphoid malignancies features different genomic alterations, including chromosomal translocations, amplifications, frameshift deletions, and mutations, to ultimately activate the oncogenic signaling programs that promote growth and survival [28]. Sequencing efforts have identified many E3 ubiquitin ligases that are mutated, amplified, or deleted in B-cell lymphoid malignancies, functioning either as a tumor suppressor or oncogene [29]. Importantly, the success of a proteasome inhibitor (bortezomib), in both MM and MCL, has further inspired the investigation of the biological significance of protein ubiquitylation and degradation in B-cell cancers [30], [31], [32]. Thus, the understanding of how the ubiquitylation of protein is achieved, and of the downstream molecular events, is critical for the development of therapeutic approaches. Targeting specific E3 ubiquitin ligases has garnered attention as it confers a selective advantage over a proteasome inhibitor by preventing any unwanted toxic effects on intra-cellular proteins. In this review, we will discuss a wide spectrum of E3 ligases that have been implicated in the pathogenesis of B-cell malignancies (Fig. 1 and Table 1).
    Concluding remarks BCL6, BCL2, and c-MYC are ATI-2341 synthesis oncogenes deregulated by chromosomal rearrangement and missense mutations in lymphoma arising from germinal center B-cells such as BL, FL, or GCB-DLBCL. Protein ubiquitylation adds another layer to the biology of GC lymphoma as discussed in this review. Specifically, BCL6 is overexpressed and stabilized by inactivation of FBXO11 and Pellino1-induced Lys63-polyubiquitylation. MYC is up-regulated by Smurf2-mediated activation of YY1 or by mutations of its FBXW7 degron. In addition, the substrate interaction domain of FBXO10 is disrupted to impair the proteasomal degradation of BCL2. Thus, different lymphoma subtypes are characterized by inappropriate turnover of key cellular players for that particular stage of B-cell differentiation (Fig. 2). Although our knowledge of the biochemical and biological functions of E3 ubiquitin ligases has increased in B-cell malignancies, a deeper characterization of cell-context dependent substrate regulation and biological relevance is needed. The recent approval of a general proteasome inhibitor, VELCADE or bortezomib, has demonstrated a great efficacy for the treatment of MM and MCL [30], [31], [32]. However, toxicity and the relevant side effects, which include anemia, neuropathy, and thrombocytopenia, in addition to bortezomib resistance, make this drug imperfect [139], [140], [141]. Recent discoveries have shown that thalidomide-based drugs target Cereblon (CRBN) [142], a member of the CULLIN4 E3 ubiquitin ligase complex, to promote proteasomal degradation of specific targets [143], [144]. This promising area of research has shown the achievement of higher drug potency, resulting in the rapid destabilization of targets via ubiquitin-dependent proteasomal degradation.
    Disclosure of potential conflicts of interest
    Acknowledgments This work was supported in part by grant R00-CA166181-04, R01-CA207513-01 from the National Cancer Institute and Gilead Sciences Research Scholars Program in Hematology/Oncology to L.B
    Introduction Atherosclerosis is the number one cause of death in the United States and among the leading causes of morbidity and mortality globally [1]. Inflammation is critical in all stages of atherosclerosis from the formation of a plaque in the vessel wall to its eventual rupture resulting in coronary ischemia, stroke, or peripheral arterial occlusion [[2], [3], [4], [5]]. Therapies that lower circulating low-density lipoprotein (LDL) levels form the cornerstone of atherosclerosis treatment. However, as inflammation has been increasingly implicated in the pathogenesis of atherosclerosis, a new genus of anti-inflammatory therapies has emerged that may provide additional therapeutic benefit beyond LDL reduction [2]. One such anti-inflammatory agent is Canakinumab, a monoclonal antibody that targets interleukin-1β. In a recent clinical trial patients already treated with LDL lowering agents experienced a 15% reduction in recurrent cardiovascular events without any change in circulating LDL levels when administered Canakinumab rather than placebo, providing proof-of-concept and validation of targeted anti-inflammatory therapies for atherosclerosis [6,7]. Because agents like Canakinumab work independent of LDL levels they have the potential to add a new dimension to the treatment of atherosclerosis beyond LDL reduction. These developments underscore the critical need for further investigation of the modulators of the inflammatory response in atherosclerosis and how they can be targeted by novel anti-inflammatory agents [7].