Selective antisense oligonucleotide inhibition of human IRF4 prevents malignant myeloma regeneration via cell cycle disruption.

Autor:	Mondala PK; Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Vora AA; Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Zhou T; Ionis Pharmaceuticals, Carlsbad, CA 92008, USA., Lazzari E; Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Ladel L; Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Luo X; Ionis Pharmaceuticals, Carlsbad, CA 92008, USA., Kim Y; Ionis Pharmaceuticals, Carlsbad, CA 92008, USA., Costello C; Moores Cancer Center at University of California, San Diego, La Jolla, CA 92093, USA; Division of Blood and Marrow Transplantation, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., MacLeod AR; Ionis Pharmaceuticals, Carlsbad, CA 92008, USA. Electronic address: rmacleod@ionisph.com., Jamieson CHM; Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center at University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: cjamieson@ucsd.edu., Crews LA; Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center at University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: lcrews@ucsd.edu.
Jazyk:	angličtina
Zdroj:	Cell stem cell [Cell Stem Cell] 2021 Apr 01; Vol. 28 (4), pp. 623-636.e9. Date of Electronic Publication: 2021 Jan 20.
DOI:	10.1016/j.stem.2020.12.017
Abstrakt:	In multiple myeloma, inflammatory and anti-viral pathways promote disease progression and cancer stem cell generation. Using diverse pre-clinical models, we investigated the role of interferon regulatory factor 4 (IRF4) in myeloma progenitor regeneration. In a patient-derived xenograft model that recapitulates IRF4 pathway activation in human myeloma, we test the effects of IRF4 antisense oligonucleotides (ASOs) and identify a lead agent for clinical development (ION251). IRF4 overexpression expands myeloma progenitors, while IRF4 ASOs impair myeloma cell survival and reduce IRF4 and c-MYC expression. IRF4 ASO monotherapy impedes tumor formation and myeloma dissemination in xenograft models, improving animal survival. Moreover, IRF4 ASOs eradicate myeloma progenitors and malignant plasma cells while sparing normal human hematopoietic stem cell development. Mechanistically, IRF4 inhibition disrupts cell cycle progression, downregulates stem cell and cell adhesion transcript expression, and promotes sensitivity to myeloma drugs. These findings will enable rapid clinical development of selective IRF4 inhibitors to prevent myeloma progenitor-driven relapse. Competing Interests: Declaration of interests T.Z., X.L., Y.K., and A.R.M. are current or past employees of Ionis Pharmaceuticals and Ionis has filed an international patent application related to this work. All other authors declare no competing interests. (Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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