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This study reveals that alternative splicing of the HTLV-1 viral gene hbz plays a critical role in causing adult T-cell leukemia/lymphoma (ATL), a highly aggressive blood cancer. Researchers found that the spliced isoform HBZ_SP1 is over 200-fold enriched in CD4 T cells from ATL patients compared to the unspliced form, and only this spliced version drives cancer cell transformation and resistance to chemotherapy. Two host proteins, hnRNPA1 and hnRNPH1, antagonistically regulate hbz splicing, with the virus hijacking this regulatory system by suppressing hnRNPA1 to favor production of the cancer-causing HBZ_SP1 isoform.
Why it matters
This discovery identifies a previously unknown mechanism by which viruses can cause cancer through manipulation of host RNA splicing machinery. The findings suggest that targeting HBZ splicing or its regulatory proteins hnRNPA1 and hnRNPH1 could offer new therapeutic strategies for ATL, a disease that remains largely untreatable with current therapies.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.
Source: Antagonistic regulation of HBZ splicing by hnRNPA1 and hnRNPH1 drives HTLV-1 leukemogenesis.