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<p>Circular RNAs constitute an emerging area of intensive research in cancer. In T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematologic malignancy characterized by clonal proliferation of T-cell precursors, the function of most aberrantly expressed circRNAs is not yet understood. To identify circRNAs acting as miRNA sponges, we performed AGO2 immunoprecipitation and RNA sequencing (AGO2-RIP-seq) in four T-ALL cell lines. Our analysis revealed circRNAs consistently enriched in the AGO2-bound fraction, highlighting a new resource for T-ALL research. Notably, circRNAs were more enriched (7.3%) compared to linear RNAs (3%). For functional investigation, we focused on the most abundant AGO2-bound circRNAs that were also found to be dysregulated in T-ALL patients. Knockdown of circN4BP2L2 revealed its ability to promote cell proliferation and confer resistance to apoptosis in T-ALL cell lines, in addition to modulating key T-ALL pathogenic pathways. Analysis of gene expression of T-ALL patients disclosed peculiar features of T-ALL with high circN4BP2L2 expression. A marked overlap was observed between differentially expressed genes upon knockdown of circN4BP2L2 in vitro and the profiles of circN4BP2L2 stratified T-ALL cases. This work provides new insights into the circRNA-mediated regulatory networks driving this malignancy and presents circN4BP2L2 as a key RNA shaping oncogenic phenotype in T-ALL.</p>

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Systematic profiling of AGO2-associated circRNAs and functional investigation reveal circN4BP2L2 as a survival-promoting regulator in T-ALL

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月27日

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  • Monika Drobna-Sledzinska,
  • Alessia Buratin,
  • Eleonora Roncaglia,
  • Alberto Caregari,
  • Ilias Glogovitis,
  • Maria Kosmalska,
  • Xing Zhao,
  • Silvia Bresolin,
  • Enrico Gaffo,
  • Anke Van den Berg,
  • Joost Kluiver,
  • Malgorzata Dawidowska,
  • Stefania Bortoluzzi

摘要

Circular RNAs constitute an emerging area of intensive research in cancer. In T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematologic malignancy characterized by clonal proliferation of T-cell precursors, the function of most aberrantly expressed circRNAs is not yet understood. To identify circRNAs acting as miRNA sponges, we performed AGO2 immunoprecipitation and RNA sequencing (AGO2-RIP-seq) in four T-ALL cell lines. Our analysis revealed circRNAs consistently enriched in the AGO2-bound fraction, highlighting a new resource for T-ALL research. Notably, circRNAs were more enriched (7.3%) compared to linear RNAs (3%). For functional investigation, we focused on the most abundant AGO2-bound circRNAs that were also found to be dysregulated in T-ALL patients. Knockdown of circN4BP2L2 revealed its ability to promote cell proliferation and confer resistance to apoptosis in T-ALL cell lines, in addition to modulating key T-ALL pathogenic pathways. Analysis of gene expression of T-ALL patients disclosed peculiar features of T-ALL with high circN4BP2L2 expression. A marked overlap was observed between differentially expressed genes upon knockdown of circN4BP2L2 in vitro and the profiles of circN4BP2L2 stratified T-ALL cases. This work provides new insights into the circRNA-mediated regulatory networks driving this malignancy and presents circN4BP2L2 as a key RNA shaping oncogenic phenotype in T-ALL.