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Selective Antisense Oligonucleotide Inhibition of Human IRF4 Prevents Malignant Myeloma Regeneration Via Cell Cycle Disruption

58 Pages Posted: 4 Aug 2020 Publication Status: Review Complete

See all articles by Phoebe K. Mondala

Phoebe K. Mondala

University of California, San Diego (UCSD) - Division of Regenerative Medicine

Ashni A. Vora

University of California, San Diego (UCSD) - Division of Regenerative Medicine

Tianyuan Zhou

Ionis Pharmaceuticals

Elisa Lazzari

University of California, San Diego (UCSD) - Division of Regenerative Medicine

Luisa Ladel

University of California, San Diego (UCSD) - Division of Regenerative Medicine

Xiaolin Luo

Ionis Pharmaceuticals

Youngsoo Kim

Ionis Pharmaceuticals

Caitlin Costello

University of California, San Diego (UCSD) - Moores Cancer Center

Robert Macleod

Ionis Pharmaceuticals

Catriona HM Jamieson

University of California, San Diego (UCSD) - Division of Regenerative Medicine

Leslie Crews

University of California, San Diego (UCSD) - Division of Regenerative Medicine

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Abstract

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

Suggested Citation

Mondala, Phoebe K. and Vora, Ashni A. and Zhou, Tianyuan and Lazzari, Elisa and Ladel, Luisa and Luo, Xiaolin and Kim, Youngsoo and Costello, Caitlin and Macleod, Robert and Jamieson, Catriona HM and Crews, Leslie, Selective Antisense Oligonucleotide Inhibition of Human IRF4 Prevents Malignant Myeloma Regeneration Via Cell Cycle Disruption. Available at SSRN: https://ssrn.com/abstract=3650570 or http://dx.doi.org/10.2139/ssrn.3650570
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Phoebe K. Mondala

University of California, San Diego (UCSD) - Division of Regenerative Medicine ( email )

United States

Ashni A. Vora

University of California, San Diego (UCSD) - Division of Regenerative Medicine ( email )

United States

Tianyuan Zhou

Ionis Pharmaceuticals

United States

Elisa Lazzari

University of California, San Diego (UCSD) - Division of Regenerative Medicine ( email )

United States

Luisa Ladel

University of California, San Diego (UCSD) - Division of Regenerative Medicine ( email )

United States

Xiaolin Luo

Ionis Pharmaceuticals

United States

Youngsoo Kim

Ionis Pharmaceuticals ( email )

United States

Caitlin Costello

University of California, San Diego (UCSD) - Moores Cancer Center

1503, 3855 Health Sciences Dr.
La Jolla, CA 92093
United States

Robert Macleod

Ionis Pharmaceuticals ( email )

United States

Catriona HM Jamieson

University of California, San Diego (UCSD) - Division of Regenerative Medicine ( email )

United States

Leslie Crews (Contact Author)

University of California, San Diego (UCSD) - Division of Regenerative Medicine ( email )

United States

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