Feed-forward regulatory loop driven by IRF4 and NF-κB in adult T-cell leukemia/lymphoma

Abstract

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive hematological malignancy derived from mature CD4+ T-lymphocytes. Here, we demonstrate the transcriptional regulatory network driven by 2 oncogenic transcription factors, IRF4 and NF-κB, in ATL cells. Gene expression profiling of primary ATL samples demonstrated that the IRF4 gene was more highly expressed in ATL cells than in normal T cells. Chromatin immunoprecipitation sequencing analysis revealed that IRF4-bound regions were more frequently found in super-enhancers than in typical enhancers. NF-κB was found to co-occupy IRF4-bound regulatory elements and formed a coherent feed-forward loop to coordinately regulate genes involved in T-cell functions and development. Importantly, IRF4 and NF-κB regulated several cancer genes associated with super-enhancers in ATL cells, including MYC, CCR4, and BIRC3. Genetic inhibition of BIRC3 induced growth inhibition in ATL cells, implicating its role as a critical effector molecule downstream of the IRF4-NF-κB transcriptional network.

DNA methylation‐mediated silencing of microRNA‐204 enhances T cell acute lymphoblastic leukemia by up‐regulating MMP‐2 and MMP‐9 via NF‐κB

“…Indeed, NF‐ĸB signalling is an important pathway in T‐ALL cells, whereby sirtuin1 can physically interact with and deacetylate the NF‐ĸB subunit of p65/RELA at lysine 310 residue, thus resulting in transcriptional inhibition 7 . Moreover, NF‐κB which is recognized as an important factor in normal inflammatory, immune and carcinogenesis, is found to be activated in T‐ALL 8 . Importantly, activation of NF‐κB in cancer‐associated leucocytes drives cytokine secretion that facilitates metastasis via activation of the C‐X‐C chemokine receptor type 7 (CXCR7) 9 .…”

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

“…In ATLL cells, somatic mutations are frequently found in genes in the TCR signaling pathway [ 7 ]. These mutations precede development of detectable disease, can accumulate in predominant clones over many years, are not found in HTLV-1 infected patients who fail to develop ATLL [ 11 ] and signal though NFκB to interferon regulatory factor 4 (IRF4) [ 12 ]. The IRF4 gene is the most frequently mutated gene in ATLL, with 1 in 4 patients carrying amplification of the IRF4 gene and 1 in 7 individuals acquiring activating nucleotide variants [ 7 ].…”

“…Highly expressed in ATLL, IRF4 drives cellular proliferation [ 13 , 14 ] and is associated with poor prognosis and therapeutic resistance [ 15 , 16 ]. IRF4 and NFκB have been described as master regulators of transcription in ATLL, forming a coherent feed-forward loop that drives cell proliferation and survival [ 12 ]. The downstream targets of IRF4 and its mechanism of action in ATLL pathogenesis remains largely uncharacterized.…”

Loss of interleukin-10 activates innate immunity to eradicate adult T-cell leukemia-initiating cells

“…Furthermore, besides its potential immunosuppressive properties (31), IL-10 promotes proliferation of HTLV-1-infected cells through the STAT3 and IRF4 pathways (25). Interestingly, it was demonstrated that IRF4 and NF-κB drive ATL maintenance (32). Similarly, a recent study showed that the HTLV-1 anti-sense bZIP factor HBZ upregulates expression of IL-10, interacts with STAT1 and STAT3 and modulates the IL-10/JAK/STAT signaling pathway (33).…”