Dissertation/Thesis Abstract

Targeting Neutrophil Extracellular Traps in Multiple Myeloma
by Li, Marina Anne, Ph.D., University of the Sciences in Philadelphia, 2019, 103; 13898249
Abstract (Summary)

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.

Indexing (document details)
Advisor: Nefedova, Yulia
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
Publication Number: 13898249
ISBN: 9781085647625
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