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<p>PAX5 acts as a master regulator of B-cell proliferation and differentiation. Its germline and somatic deregulation have both been implicated in the development of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, the process how reduced <i>PAX5</i> transcriptional activity mediates progression to BCP-ALL, is still poorly understood. Here, we characterized the longitudinal effects of PAX5 reduction on healthy, pre-leukemic and BCP-ALL cells at the single-cell level. Cell-surface marker analysis revealed a genotype-driven enrichment of the pre-BII population in healthy <i>Pax5</i><sup>±</sup> mice. This population showed downregulated B-cell receptor signaling, while DNA replication/repair and cell-cycle signaling pathways were upregulated. Moreover, we observed a shift in the kappa/lambda light chain ratio toward lambda rearranged B-cells. Transplantation experiments further validated a delay of <i>Pax5</i><sup>±</sup> pre-BII cells in maturation and transition to IgM-positivity. Additionally, single-cell RNA-Sequencing and bulk ATAC-Sequencing of different stages of BCP-ALL evolution showed that <i>Pax5</i><sup>±</sup> pre-leukemic cells lose their B-cell identity and display <i>Myc</i> activation. Subsequently, BCP-ALLs acquired additional RAG-mediated aberrations and driver mutations in JAK-STAT and RAS-signaling pathways. Together, this study elucidates molecular and functional checkpoints in PAX5-mediated pre-leukemic cell progression exploitable for therapeutic intervention and demonstrates that PAX5 reduction is sufficient to initiate clonal evolution to BCP-ALL through activation of MYC.</p><p></p>

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Trajectories from single-cells to PAX5-driven leukemia reveal PAX5-MYC interplay in vivo

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月20日

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  • Franziska Auer,
  • Mina N. F. Morcos,
  • Mikko Sipola,
  • Irfan Akhtar,
  • Sanni Moisio,
  • Julia Vogt,
  • Rebecca Haag,
  • Mari Lahnalampi,
  • Tiina J. Tuononen,
  • Andrea Hanel,
  • Anna Viitasalo,
  • Ulrike A. Friedrich,
  • Andreas Dahl,
  • Carolin Prexler,
  • Aleksandra A. Pandyra,
  • Polina Stepensky,
  • Masatoshi Takagi,
  • Arndt Borkhardt,
  • Merja Heinäniemi,
  • Julia Hauer

摘要

PAX5 acts as a master regulator of B-cell proliferation and differentiation. Its germline and somatic deregulation have both been implicated in the development of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, the process how reduced PAX5 transcriptional activity mediates progression to BCP-ALL, is still poorly understood. Here, we characterized the longitudinal effects of PAX5 reduction on healthy, pre-leukemic and BCP-ALL cells at the single-cell level. Cell-surface marker analysis revealed a genotype-driven enrichment of the pre-BII population in healthy Pax5± mice. This population showed downregulated B-cell receptor signaling, while DNA replication/repair and cell-cycle signaling pathways were upregulated. Moreover, we observed a shift in the kappa/lambda light chain ratio toward lambda rearranged B-cells. Transplantation experiments further validated a delay of Pax5± pre-BII cells in maturation and transition to IgM-positivity. Additionally, single-cell RNA-Sequencing and bulk ATAC-Sequencing of different stages of BCP-ALL evolution showed that Pax5± pre-leukemic cells lose their B-cell identity and display Myc activation. Subsequently, BCP-ALLs acquired additional RAG-mediated aberrations and driver mutations in JAK-STAT and RAS-signaling pathways. Together, this study elucidates molecular and functional checkpoints in PAX5-mediated pre-leukemic cell progression exploitable for therapeutic intervention and demonstrates that PAX5 reduction is sufficient to initiate clonal evolution to BCP-ALL through activation of MYC.