Baccini, V. | Search bioRxiv

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↗

bioRxiv2020

Modulation of sleep-courtship balance by nutritional status in Drosophila

Sleep is essential but incompatible with other behaviors, and thus sleep drive competes with other motivations. We previously showed Drosophila males balance sleep and courtship via octopaminergic neurons that act upstream of courtship-regulating P1 neurons (Machado et al., 2017). Here we show nutrition modulates the sleep-courtship balance and identify sleep-regulatory neurons downstream of P1 neurons. Yeast-deprived males exhibited attenuated female-induced nighttime sleep loss yet normal daytime courtship, which suggests male flies consider nutritional status in deciding whether the potential benefit of pursuing female partners outweighs the cost of losing sleep. Trans-synaptic tracing and calcium imaging identified dopaminergic neurons projecting to the protocerebral bridge (DA-PB) as postsynaptic partners of P1 neurons. Activation of DA-PB neurons led to reduced sleep in normally fed but not yeast-deprived males. Additional PB-projecting neurons regulated male sleep, suggesting several groups of PB-projecting neurons act downstream of P1 neurons to mediate nutritional modulation of the sleep-courtship balance.

neuroscience↗