Biology subjects

Cesaire, R.

Publications and source records attributed to Cesaire, R..

3 recordsLinked to original sources

bioRxiv2026

Transcriptional rewiring of NF-κB by HBZ and Fra-2 drives inflammatory chemoresistance in Tax-negative adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATL) is an aggressive HTLV-1-associated malignancy with poor responses to chemotherapy. Although constitutive NF-kB activation is a hallmark of ATL, its persistence in tax-negative (Type I) ATL, where Tax is irreversibly silenced, remains unresolved. Here, we identify Fra-2 as a coactivator of NF-kB p65 that redirects p65's transcriptional activity toward inflammatory genes. Mechanistically, Fra-2 interacts with the Rel homology domain of p65 via its bZIP domain, enhancing p65 DNA-binding activity without altering nuclear localization. The HTLV-1 antisense protein HBZ disrupts Fra-2/JunD AP-1 complexes while stabilizing Fra-2/p65, as shown by co-immunoprecipitation, BiFC, and PICO assays. This rewiring selectively enhances NF-kB-dependent transcription of IL-1b, which is elevated in ATL patient sera and cells independently of proviral load. Chromatin immunoprecipitation revealed Fra-2 recruitment to NF-kB response elements in the IL1b promoter, an effect amplified by HBZ. Pharmacological inhibition of IL-1 signaling with anakinra or anti-IL-1b antibodies restored doxorubicin sensitivity in primary ATL cells. Together, these findings establish the Fra-2-NF-kB-IL-1b axis as a driver of chemoresistance in tax-negative ATL and a therapeutically targetable vulnerability.

cancer biology↗

bioRxiv2026

Antagonistic regulation of HBZ splicing by hnRNPA1 and hnRNPH1 drives HTLV-1 leukemogenesis.

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive leukemia driven by Human T-cell Leukemia Virus type 1 (HTLV-1) and remains largely refractory to current therapies. Although hbz is the only viral transcript consistently expressed in acute ATL, the extent to which its alternative splicing shapes disease biology remains unknown. Here, we demonstrate that the splicing of hbz plays a key role in driving cancer development in ATL. Quantitative analyses in HTLV-1-infected cell lines and primary samples revealed a striking enrichment of the spliced isoform HBZ_SP1 (over 200-fold) in CD4 T cells from ATL patients, whereas the unspliced transcript (usHBZ) predominates in CD8 T cells. Despite robust transcription, the usHBZ protein was undetectable, whereas HBZ_SP1 accumulated rapidly, identifying it as the main isoform in CD4 T cells from ATL patients. Furthermore, only HBZ_SP1 drove cellular transformation and conferred marked resistance to chemotherapeutic stress. Mechanistically, we identify a splicing regulatory axis centered on hnRNPA1 and hnRNPH1. Both proteins bind hbz pre-mRNA, but exert opposing effects: hnRNPA1 represses splicing, whereas hnRNPH1 promotes production of the oncogenic HBZ_SP1 isoform. Perturbation of this balance reprograms HBZ isoform expression and alters leukemic cell fitness. Collectively, our findings establish that HBZ inhibits hnRNPA1 transcription, therefore allowing HTLV-1 to hijack host RNA splicing and to generate an oncogenic isoform that drives transformation and chemoresistance. These results uncover a previously unrecognized post-transcriptional mechanism of viral leukemogenesis and position HBZ splicing and its regulators as therapeutic targets in ATL. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/739521v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@1298adorg.highwire.dtl.DTLVardef@e5a7beorg.highwire.dtl.DTLVardef@167d576org.highwire.dtl.DTLVardef@1ef68f6_HPS_FORMAT_FIGEXP M_FIG C_FIG Mechanistic model of HBZ splicing regulation. This simplified graphical abstract summarizes the highlights of our study. Here, we hypothesize that in CD4+ T cells infected by HTLV-1, transcription and splicing reprogramming lead to a preferential expression of the HBZ_SP1 oncogenic isoform, specifically due to an overexpression of the splicing activator hnRNP H1and repression of hnRNP A1 by HBZ itself via C/EBP. HBZ_SP1 is consistently expressed and then drives cell transformation and chemoresistance. In contrast, in CD8+ T cells infected with HTLV-1, the HBZ-mediated downregulation of hnRNP A1 is overcome, leading to inhibition of HBZ splicing and increased expression of the less oncogenic isoform usHBZ.

molecular biology↗

bioRxiv2019

Prevalence of chronic chikungunya and associated risks factors in the French West Indies (La Martinique). A prospective cohort study

BackgroundThe chikungunya virus (CHIKV) is a re-emerging alphavirus that can cause chronic rheumatic musculoskeletal disorders, named chronic chikungunya (CHIKC+), which may be long-term incapacitating. A chikungunya outbreak occurred in 2013 in La Martinique. We constituted the first prospective cohort study of CHIKV-infected subjects in the Caribbean to assess the prevalence of CHIKC+ at 12 months and to search for factors present at the acute stage significantly associated with chronicity.\n\nMethodology/Principal findingsA total of 193 patients who tested positive for RT-PCR CHIKV, were submitted to clinical investigations in the acute phase (<21 days), and 3, 6, and 12 months after their inclusion. A total of 167 participants could be classified as either suffering or not from CHIKC+. They were analyzed using logistic regression models. At 12 months, the overall prevalence of CHIKC+ was 52.1% (95%CI: 44.5-59.7). In univariate analysis, age (OR: 1.04; 95% CI: 1.02-1.07; p=0.0003), being male (OR: 0.51; 95%CI: 0.27-0.98; p=0.04), headache (OR: 1.90; 95%CI: 1.02-3.56; p=0.04), vertigo (OR: 2.06; 95%CI: 1.05-4.03; p=0.04), vomiting (OR: 2.51; 95%CI: 1.07-5.87; p = 0.03), urea (OR: 1.33; 95%CI: 1.05-1.70; p=0.02) were associated with CHIKC+. In final multivariate logistic regression models for 167 participants, predictors of CHIKC+ were age (OR 1.06; 95%CI: 1.03-1.08; p<0.0001), male sex (OR: 0.40; 95%CI: 0.19-0.84; p=0.015), vertigo (OR: 2.46; 95%CI: 1.16-5.20; p=0.019), hypotension (OR 4.72; 95% -CI: 1.19-18.79; p=0.028), recoloration time >3 seconds (OR: 3.79; 95%-CI: 1.01-14.25).\n\nConclusionsThis cohort study in La Martinique confirms that CHIKC+ is a frequent complication of acute chikungunya disease. Analysis emphasized the importance of age and female sex for CHIKC occurrence, and pointed out the potential aggravating role of dehydration at the acute phase. Early and adequate hydration could reduce the risk chronic chikungunya disorders.\n\nAuthor SummaryChikungunya is a mosquito-borne virus found in tropical countries that has been re-emerging in the last decade. It has caused major epidemics in recent years, such as in Reunion Island and in Southeast Asia. Nearly 2.5 billion people around the world are at risk of contracting the virus. During the acute phase of the illness, patients experience a flu-like syndrome with fever, headache, myalgia, rash, and severe arthralgia. These symptoms can persist for several months in some patients, and can lead to significant functional disability. During the 2013 epidemic in Martinique, we followed nearly 200 patients who had contracted chikungunya. More than half of the patients had a chronic form of the disease--mainly women over 50 years of age. Our statistical analyses indicate that poor hydration during the acute phase may be a risk factor for developing chronic rheumatism. Therefore, in the context of a chikungunya epidemic, it seems important to encourage patients to drink plenty of fluids as soon as the first symptoms appear.

microbiology↗