Interferon regulatory factor 4 as a therapeutic target in adult T-cell leukemia lymphoma

Daniel A Rauch,A Robert Macleod,Grant Challen,Lee Ratner,John C Harding,Tianyuan Zhou,Hemalatha Sundaramoorthi,Sydney L Olson,Youngsoo Kim

doi:10.1186/s12977-020-00535-z

Abstract

BackgroundAdult T-cell leukemia lymphoma (ATLL) is a chemotherapy-resistant malignancy with a median survival of less than one year that will afflict between one hundred thousand and one million individuals worldwide who are currently infected with human T-cell leukemia virus type 1. Recurrent somatic mutations in host genes have exposed the T-cell receptor pathway through nuclear factor κB to interferon regulatory factor 4 (IRF4) as an essential driver for this malignancy. We sought to determine if IRF4 represents a therapeutic target for ATLL and to identify downstream effectors and biomarkers of IRF4 signaling in vivo.ResultsATLL cell lines, particularly Tax viral oncoprotein-negative cell lines, that most closely resemble ATLL in humans, were sensitive to dose- and time-dependent inhibition by a next-generation class of IRF4 antisense oligonucleotides (ASOs) that employ constrained ethyl residues that mediate RNase H-dependent RNA degradation. ATLL cell lines were also sensitive to lenalidomide, which repressed IRF4 expression. Both ASOs and lenalidomide inhibited ATLL proliferation in vitro and in vivo. To identify biomarkers of IRF4-mediated CD4 + T-cell expansion in vivo, transcriptomic analysis identified several genes that encode key regulators of ATLL, including interleukin 2 receptor subunits α and β, KIT ligand, cytotoxic T-lymphocyte-associated protein 4, and thymocyte selection-associated high mobility group protein TOX 2.ConclusionsThese data support the pursuit of IRF4 as a therapeutic target in ATLL with the use of either ASOs or lenalidomide.

Highlights

Adult T-cell leukemia lymphoma (ATLL) is a chemotherapy-resistant malignancy with a median survival of less than one year that will afflict between one hundred thousand and one million individuals worldwide who are currently infected with human T-cell leukemia virus type 1
Proliferation of Tax‐negative ATLL cell lines is dependent on interferon regulatory factor 4 (IRF4) Antisense oligonucleotides (ASOs) that directly target IRF4 messenger RNA were used to silence IRF4 gene expression in ATLL cell lines, primary patient-derived ATLL cells, and control cell T-cell lines
Proliferation of ATLL cells that express the Tax oncogene was largely resistant to the suppression of IRF4, whereas the proliferation of Tax-negative cells was exquisitely sensitive to IRF4 knockdown in a dose-dependent (Fig. 1b) and time-dependent (Fig. 1c) manner

Summary

Introduction

Adult T-cell leukemia lymphoma (ATLL) is a chemotherapy-resistant malignancy with a median survival of less than one year that will afflict between one hundred thousand and one million individuals worldwide who are currently infected with human T-cell leukemia virus type 1. Tax induces cell proliferation through T-cell receptor (TCR) signaling to nuclear factor κB (NFκB), confers resistance to apoptosis, and promotes genetic instability, all of which contribute to the initiation of T-cell malignancy [8]. These functions are mediated by the effect of Tax on an array of cellular proteins, described as the “Tax interactome” [9]. Tax is highly immunogenic and cells expressing it at high levels are targeted by cytotoxic T lymphocytes (CTL) [10] This results in selection of ATLL cells that suppress Tax and compensate for loss of Tax by acquiring genetic or epigenetic changes in the Tax interactome [7]

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Conclusion