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Background <p>Diffuse large B-cell lymphoma (DLBCL) remains the most common and aggressive subtype of non-Hodgkin lymphoma. However, a significant proportion of patients relapses or becomes refractory to standard R-CHOP therapy. Long non-coding RNAs (lncRNAs) have emerged as key regulators in tumorigenesis, but the role of RPARP-AS1 and its downstream molecular mechanisms in DLBCL remains undefined.</p> Methods <p>To elucidate the function of RPARP-AS1 in DLBCL, its expression was analyzed in patient tissues, DLBCL cell lines, and public datasets. Functional effects of RPARP-AS1 were examined through loss- and gain-of-function experiments in SU-DHL-6 and U2932 cells, and DLBCL cell proliferation, apoptosis, invasion, and epithelial-mesenchymal transition (EMT) were assessed. A xenograft mouse model was used to validate in vivo tumorigenicity. Mechanistic studies were conducted to determine whether RPARP-AS1 exerts transcriptional regulation by interacting with the transcription factor ETV2 and modulating APOM expression, integrating luciferase reporter, RNA immunoprecipitation, RNA pull-down, and chromatin immunoprecipitation assays. Additionally, we explored the effects of R-CHOP treatment alone or in combination with si-RPARP-AS1 on DLBCL cells.</p> Results <p>RPARP-AS1 was markedly upregulated and predominantly localized in the nucleus of DLBCL cells. Silencing RPARP-AS1 inhibited cell proliferation and invasion, induced apoptosis, suppressed EMT in vitro, and significantly reduced tumor growth in vivo. Mechanistically, RPARP-AS1 directly bound to ETV2, enhanced its nuclear accumulation as well as binding to the APOM promoter, and transcriptionally activated APOM expression. Functionally, APOM overexpression rescued the RPARP-AS1 knockdown on DLBCL cell phenotypes as well as the PI3K/AKT pathway, confirming APOM as a downstream effector of RPARP-AS1. Moreover, RPARP-AS1 silencing was revealed to potentiate the anti-tumor efficacy of R-CHOP regimen in DLBCL.</p> Conclusions <p>RPARP-AS1 acts as a nuclear oncogenic lncRNA that promotes DLBCL progression by facilitating ETV2-mediated transcriptional activation of APOM. The RPARP-AS1/ETV2/APOM axis represents a novel regulatory pathway contributing to DLBCL malignancy and may serve as a promising therapeutic target for refractory disease.</p>

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LncRNA RPARP-AS1 drives diffuse large B-cell lymphoma progression through ETV2-mediated transcriptional activation of APOM

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月30日

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  • Jia Liu,
  • Ling Duan,
  • Yujuan Niu,
  • Shengde Zhu,
  • Xinlian Zhang

摘要

Background

Diffuse large B-cell lymphoma (DLBCL) remains the most common and aggressive subtype of non-Hodgkin lymphoma. However, a significant proportion of patients relapses or becomes refractory to standard R-CHOP therapy. Long non-coding RNAs (lncRNAs) have emerged as key regulators in tumorigenesis, but the role of RPARP-AS1 and its downstream molecular mechanisms in DLBCL remains undefined.

Methods

To elucidate the function of RPARP-AS1 in DLBCL, its expression was analyzed in patient tissues, DLBCL cell lines, and public datasets. Functional effects of RPARP-AS1 were examined through loss- and gain-of-function experiments in SU-DHL-6 and U2932 cells, and DLBCL cell proliferation, apoptosis, invasion, and epithelial-mesenchymal transition (EMT) were assessed. A xenograft mouse model was used to validate in vivo tumorigenicity. Mechanistic studies were conducted to determine whether RPARP-AS1 exerts transcriptional regulation by interacting with the transcription factor ETV2 and modulating APOM expression, integrating luciferase reporter, RNA immunoprecipitation, RNA pull-down, and chromatin immunoprecipitation assays. Additionally, we explored the effects of R-CHOP treatment alone or in combination with si-RPARP-AS1 on DLBCL cells.

Results

RPARP-AS1 was markedly upregulated and predominantly localized in the nucleus of DLBCL cells. Silencing RPARP-AS1 inhibited cell proliferation and invasion, induced apoptosis, suppressed EMT in vitro, and significantly reduced tumor growth in vivo. Mechanistically, RPARP-AS1 directly bound to ETV2, enhanced its nuclear accumulation as well as binding to the APOM promoter, and transcriptionally activated APOM expression. Functionally, APOM overexpression rescued the RPARP-AS1 knockdown on DLBCL cell phenotypes as well as the PI3K/AKT pathway, confirming APOM as a downstream effector of RPARP-AS1. Moreover, RPARP-AS1 silencing was revealed to potentiate the anti-tumor efficacy of R-CHOP regimen in DLBCL.

Conclusions

RPARP-AS1 acts as a nuclear oncogenic lncRNA that promotes DLBCL progression by facilitating ETV2-mediated transcriptional activation of APOM. The RPARP-AS1/ETV2/APOM axis represents a novel regulatory pathway contributing to DLBCL malignancy and may serve as a promising therapeutic target for refractory disease.