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An activating mutation of interferon regulatory factor 4 (IRF4) in adult T cell leukemia.

An activating mutation of interferon regulatory factor 4 (IRF4) in adult T cell leukemia.
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Cherian MA, Olson S, Sundaramoorthi H, Cates K, Cheng X, Harding J, Martens A, Challen GA, Tyagi M, Ratner L, Rauch D,


Cherian MA, Olson S, Sundaramoorthi H, Cates K, Cheng X, Harding J, Martens A, Challen GA, Tyagi M, Ratner L, Rauch D, (click to view)

Cherian MA, Olson S, Sundaramoorthi H, Cates K, Cheng X, Harding J, Martens A, Challen GA, Tyagi M, Ratner L, Rauch D,

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The Journal of biological chemistry 2018 03 14() pii jbc.RA117.000164
Abstract

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, likely as a result of specific immuno-editing, Tax expression is downregulated 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, and the K59R mutation is the most common single-nucleotide variation in IRF4 and is found exclusively in ATL. Here high throughput whole-exome sequencing revealed recurrent activating genetic alterations in the T cell receptor, CD28, and NF-kB pathways. Moreover, 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 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 is wild-type IRF4, and is transcriptionally more active. Expression of both wild-type 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 since ATL cells select for a mutant of IRF4 with higher nuclear expression and transcriptional activity, and over-expression of IRF4 induces the expansion of T lymphocytes in vivo.

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