Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 293, Issue 18, Pages 6844-6858Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA117.000164
Keywords
interferon regulatory factor (IRF); retrovirus; chromatin immunoprecipitation (ChiP); NF-kappaB transcription factor; cancer biology; ATL; HTLV; driver mutation
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Funding
- NCI, National Institutes of Health (NIH), Cancer Center Support Grant [P30 CA91842]
- ICTS/CTSA Grant from the National Center for Research Resources (NCRR), a component of NIH [UL1 TR000448]
- NIH Roadmap for Medical Research
- NATIONAL CANCER INSTITUTE [P30CA091842, P50CA094056, P01CA100730, R01CA063417, K12CA167540] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR002345, UL1TR000448] Funding Source: NIH RePORTER
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The human T-cell leukemia virus-1 (HTLV-1) oncoprotein Tax drives cell proliferation and resistance to apoptosis early in the pathogenesis of adult T-cell leukemia (ATL). Subsequently, probably as a result of specific immunoediting, Tax expression is down-regulated and functionally replaced by somatic driver mutations of the host genome. Both amplification and point mutations of interferon regulatory factor 4 (IRF4) have been previously detected in ATL., K59R is the most common single-nucleotide variation of IRF4 and is found exclusively in ATL. High-throughput whole-exome sequencing revealed recurrent activating genetic alterations in the T-cell receptor, CD28, and NF-B pathways. We found that IRF4, which is transcriptionally activated downstream of these pathways, is frequently mutated in ATL. IRF4 RNA, protein, and IRF4 transcriptional targets are uniformly elevated in HTLV-1-transformed cells and ATL cell lines, and IRF4 was bound to genomic regulatory DNA of many of these transcriptional targets in HTLV-1-transformed cell lines. We further noted that the K59R IRF4 mutant is expressed at higher levels in the nucleus than WT IRF4 and is transcriptionally more active. Expression of both WT and the K59R mutant of IRF4 from a constitutive promoter in retrovirally transduced murine bone marrow cells increased the abundance of T lymphocytes but not myeloid cells or B lymphocytes in mice. IRF4 may represent a therapeutic target in ATL because ATL cells select for a mutant of IRF4 with higher nuclear expression and transcriptional activity, and overexpression of IRF4 induces the expansion of T lymphocytes in vivo.
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