Selective Antisense Oligonucleotide Inhibition of Human IRF4 Prevents Malignant Myeloma Regeneration Via Cell Cycle Disruption
58 Pages Posted: 4 Aug 2020 Publication Status: Review CompleteMore...
In multiple myeloma, pro-inflammatory factors such as interleukin-6 signaling and downstream anti-viral response pathway activation have been correlated with disease progression, symptom severity, and cancer stem cell generation. However, the role of interferon-response factors in the maintenance of malignant progenitors has not been explored. We hypothesized that the key B-cell progenitor fate determinant, interferon-response factor-4 (IRF4), governs regeneration of drug-resistant malignant progenitors in multiple myeloma. Using diverse pre-clinical models, including a humanized in vivo model that recapitulates IRF4 pathway activation detected by RNA-sequencing in primary high-risk samples, we tested whether direct targeting of human IRF4 using state-of-the-art antisense oligonucleotide (ASO) agents could impair myeloma regeneration. While human IRF4 overexpression expanded a putative progenitor population in vitro, IRF4 ASO treatment impaired myeloma cell survival commensurate with reduced IRF4 and MYC gene and protein expression. In addition to impeding subcutaneous tumor formation and myeloma dissemination in xenograft immunocompromised mouse models, human IRF4-targeted ASO monotherapy significantly improved overall animal survival. Moreover, in a patient-derived mouse model of high-risk myeloma, treatment with a lead IRF4 ASO that will advance to a Phase 1 trial (NCT04398485) eradicated CD138-negative MM progenitors and their malignant plasma cell progeny at doses that spared normal human hematopoietic stem cells and B cell development. Complementary mechanistic studies uncovered a role for IRF4 inhibition in disrupting microenvironment-responsive cell cycle progression, down-regulating stem cell regulatory and cell adhesion transcript expression including MYC and CXCR4, and promoting sensitivity to standard-of-care therapeutic agents. These comprehensive therapeutic index and proof-of-concept studies will enable rapid clinical development of IRF4 inhibition to prevent myeloma relapse driven by retention of dormant, drug-resistant progenitors in inflammatory microenvironments.
Keywords: multiple myeloma; cancer stem cells; IRF4; interferon-response factor-4; MYC; CXCR4; cell cycle; antisense oligonucleotide; bone marrow; translational research
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