Multiple myeloma (MM) is a cancer of plasma cells that are overproduced in the bone marrow (BM). Within the BM, neutrophils represent the largest immune cell population, however their role in MM progression remains largely unknown. Fifteen years ago, neutrophil extracellular traps (NETs) were reported as extracellular decondensed chromatin released from activated neutrophils. Initial reports showed that NETs trap pathogens to prevent their dissemination. While NETs may be beneficial in the context of infection, increasing evidences have shown that excessive release of NETs contributes to various pathological conditions, including cancer. Various stimuli have been reported to prime neutrophils to form NETs, however the ability of MM cells to induce NET formation has not been studied. Here we showed that MM cells and MM-derived soluble factors predispose neutrophils to release NETs in vitro. We also demonstrated that neutrophils isolated from MM-bearing mice generated more NETs in response to MM cells compared with neutrophils isolated from tumor-free mice. We identified that MM cells actively released HMGB1 and showed in vitro that HMGB1 and syndecan-1 (SDC1) promoted the formation of NETs, which was dependent on Toll like receptor 4 (TLR4). Blocking HMGB1 and SDC1 inhibited MM-induced NET formation. To further understand the contribution of citrullination in NET formation we employed peptidylarginine deiminase (PAD4) deficient mice and showed absence of citrullination in stimulated neutrophils isolated from those mice. We also tested in vitro and in vivo the effects of a novel specific PAD4 inhibitor, BMS-5, provided by Bristol-Myers Squibb (BMS). We demonstrated that pharmacological inhibition of PAD4 blocked MM-induced NET formation in vitro in mouse and human neutrophils. In syngeneic model of MM, BMS-5 demonstrated anti-tumor effect. Taken together, our data indicate that targeting PAD4 in patients with MM may improve the clinical outcome of this disease.
|Commitee:||Klase, Zachary, Zhang, Rugang, Bruist, Michael, Gamero, Ana|
|School:||University of the Sciences in Philadelphia|
|Department:||Cell & Molecular Biology|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 81/2(E), Dissertation Abstracts International|
|Subjects:||Oncology, Cellular biology|
|Keywords:||Multiple myeloma, Neutrophil extracellular trap|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be