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Interferon regulatory factor 4 as a therapeutic target in adult T-cell leukemia lymphoma
- Source :
- Retrovirology, Retrovirology, Vol 17, Iss 1, Pp 1-10 (2020)
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
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.
- Subjects :
- lcsh:Immunologic diseases. Allergy
CD4-Positive T-Lymphocytes
Interleukin 2
Somatic cell
Stem cell factor
Biology
ATLL
Adult T-cell leukemia/lymphoma
ASO
Mice
03 medical and health sciences
IRF4
Cell Line, Tumor
hemic and lymphatic diseases
Virology
medicine
Animals
Humans
Leukemia-Lymphoma, Adult T-Cell
Cytotoxic T cell
Lenalidomide
Cell Proliferation
030304 developmental biology
Human T-lymphotropic virus 1
0303 health sciences
030306 microbiology
Research
Gene Products, tax
Oligonucleotides, Antisense
Thionucleotides
medicine.disease
HTLV-I Infections
Leukemia
Thymocyte
Infectious Diseases
HTLV-1
Interferon Regulatory Factors
Cancer research
lcsh:RC581-607
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 17424690
- Volume :
- 17
- Database :
- OpenAIRE
- Journal :
- Retrovirology
- Accession number :
- edsair.doi.dedup.....520f55c26f673ce5a76c169974187d77