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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics
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Cancer Biology and Translational Studies

A Novel Peptidylarginine Deiminase 4 (PAD4) Inhibitor BMS-P5 Blocks Formation of Neutrophil Extracellular Traps and Delays Progression of Multiple Myeloma

Marina Li, Cindy Lin, Hui Deng, Joann Strnad, Luca Bernabei, Dan T. Vogl, James J. Burke and Yulia Nefedova
Marina Li
1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
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Cindy Lin
1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
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Hui Deng
1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
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Joann Strnad
2Bristol-Myers Squibb, Lawrenceville, New Jersey.
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Luca Bernabei
3Division of Hematology/Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
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  • ORCID record for Luca Bernabei
Dan T. Vogl
3Division of Hematology/Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
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  • ORCID record for Dan T. Vogl
James J. Burke
2Bristol-Myers Squibb, Lawrenceville, New Jersey.
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Yulia Nefedova
1Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
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  • For correspondence: ynefedova@wistar.org
DOI: 10.1158/1535-7163.MCT-19-1020 Published July 2020
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Abstract

Multiple myeloma is a plasma cell malignancy, which grows in the bone marrow (BM). The major population of cells in the BM is represented by neutrophils and they can form neutrophil extracellular traps (NET). Here, we investigated whether multiple myeloma cells induce NET formation and whether targeting this process would delay multiple myeloma progression. We demonstrated that murine and human multiple myeloma cells stimulate citrullination of histone H3 and NET formation by neutrophils and that this process is abrogated by pharmacological targeting of peptidylarginine deiminase 4 (PAD4) with a novel-specific small molecule inhibitor BMS-P5. Administration of BMS-P5 to multiple myeloma-bearing mice delays appearance of symptoms and disease progression. Taken together, our data demonstrate that targeting PAD4 may be beneficial for treatment of multiple myeloma.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2020;19:1530–8

  • Received October 27, 2019.
  • Revision received March 25, 2020.
  • Accepted May 1, 2020.
  • Published first May 5, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (7)
July 2020
Volume 19, Issue 7
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A Novel Peptidylarginine Deiminase 4 (PAD4) Inhibitor BMS-P5 Blocks Formation of Neutrophil Extracellular Traps and Delays Progression of Multiple Myeloma
Marina Li, Cindy Lin, Hui Deng, Joann Strnad, Luca Bernabei, Dan T. Vogl, James J. Burke and Yulia Nefedova
Mol Cancer Ther July 1 2020 (19) (7) 1530-1538; DOI: 10.1158/1535-7163.MCT-19-1020

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A Novel Peptidylarginine Deiminase 4 (PAD4) Inhibitor BMS-P5 Blocks Formation of Neutrophil Extracellular Traps and Delays Progression of Multiple Myeloma
Marina Li, Cindy Lin, Hui Deng, Joann Strnad, Luca Bernabei, Dan T. Vogl, James J. Burke and Yulia Nefedova
Mol Cancer Ther July 1 2020 (19) (7) 1530-1538; DOI: 10.1158/1535-7163.MCT-19-1020
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Molecular Cancer Therapeutics
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