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

Abstract

Background 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. 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. Results ATLL 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. Conclusions These data support the pursuit of IRF4 as a therapeutic target in ATLL with the use of either ASOs or lenalidomide.

XPO1 inhibitors represent a novel therapeutic option in Adult T-cell Leukemia, triggering p53-mediated caspase-dependent apoptosis

“…Of note, the XPO1 gene module we identified in ATL patients also contained IRF4 (data not shown), which has been identified as a sensitive predictor of IFN + AZT therapy failure 20 . Therefore, IRF4-overexpressing patients 21 likely to fail first-line therapy might preferentially benefit from XPO1 targeting.…”

Targeting NF-κB with Nanotherapy in a Mouse Model of Adult T-Cell Leukemia/Lymphoma

“…Therefore, it remains crucial to develop new therapeutic approaches for slowing down or reducing tumor burden. Our recently study on NF-κB downstream interferon regulatory factor 4 (IRF4) suggested that IRF4 could be a potential therapeutic target for ATLL treatment [ 68 ]. Therefore, for the further therapeutic development, it is worth considering combination therapy that targets both NF-κB and its dependent genes, such as IRF4.…”

The molecular basis for the development of adult T‐cell leukemia/lymphoma in patients with an IRF4K59R mutation

“…6 Furthermore, treatment with either IRF4 antisense oligonucleotides (ASOs) or lenalidomide, an FDA-approved drug for multiple myeloma which indirectly affects IRF4 expression, have been shown to reduce the proliferation of ATLL cells. 1 Collectively, these studies have identified a key role for IRF4 in the pathogenesis of ATLL.…”

“…Clinically relevant arginine substitution mutations that occur within the IRF4 DNA-binding domain are also presented using individual symbols to represent the relevant disease variations (SNV). 1,17 Previous studies have shown IRF4 K59R as a recurrent somatic mutation in ATLL. In wildtype, lysine 59 lies in the DBD of IRF4 and is fairly conserved amongst the IRF family of TFs.…”

“…ATLL develops as a result of infection with human T-cell leukemia virus type 1 (HTLV-1), with approximately 5% of 20 million patients infected with of HTLV-1 developing the disease. 1 The genomic integration of HTLV-1, characteristic of ATLL, is central to disease pathogenesis, 2 with HTLV-1 driving expression of the Tax trans-activator/ oncoprotein, which in turn, results in activation of the NF-κB pathway, the critical initiator in ATLL development. 1,3 Another key HTLV-1 derived protein important for tumorigenesis is the HTLV-1 basic zipper protein (HBZ) whose expression has been shown to induce Srinivasan Sundararaj and Sandali Seneviratne contributed equally.…”