Trajectories from single-cells to PAX5-driven leukemia reveal PAX5-MYC interplay in vivo
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<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 Pax5<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 Pax5<sup>±</sup> 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.
Authors
- Andrea Hänel (ORCID: https://orcid.org/0000-0001-6022-4362)
- Masatoshi Takagi (ORCID: https://orcid.org/0000-0002-7580-9184)
- Anna Viitasalo (ORCID: https://orcid.org/0000-0002-7861-7217)
- Julie Vogt
- Polina Stepensky (ORCID: https://orcid.org/0000-0002-4923-3660)
- Franziska Auer (ORCID: https://orcid.org/0000-0002-1193-6002)
- Arndt Borkhardt (ORCID: https://orcid.org/0000-0002-6121-4737)
- Ulrike Anne Friedrich (ORCID: https://orcid.org/0000-0001-7295-4549)
- Carolin Prexler (ORCID: https://orcid.org/0000-0001-7136-0554)
- Aleksandra A. Pandyra (ORCID: https://orcid.org/0000-0003-4794-0035)
- Mina N.F. Morcos (ORCID: https://orcid.org/0000-0001-5812-9526)
- Andreas Dahl (ORCID: https://orcid.org/0000-0002-2668-8371)
- Irfan Akhtar (ORCID: https://orcid.org/0000-0003-1566-2755)
- R Haag (ORCID: https://orcid.org/0000-0001-9575-9471)
- Sanni Moisio (ORCID: https://orcid.org/0009-0009-4446-015X)
- Julia Hauer (ORCID: https://orcid.org/0000-0002-4058-3058)
- Mari Lahnalampi (ORCID: https://orcid.org/0000-0003-4050-4935)
- Mikko Sipola
- Tiina J Tuononen (ORCID: https://orcid.org/0009-0007-6677-3064)
Institutions
- University of Eastern Finland (FI)
- German Cancer Research Center (DE)
- Hebrew University of Jerusalem (IL)
- University Hospital Bonn (DE)
- Hadassah Medical Center (IL)
- German Center for Infection Research (DE)
- Center for Systems Biology Dresden (DE)
- Deutsches Diabetes-Zentrum e.V. (DE)
- German Center for Diabetes Research (DE)
- University Hospital Carl Gustav Carus (DE)
- Paul Langerhans Institute Dresden (DE)
- Heinrich Heine University Düsseldorf (DE)
- Technical University of Munich (DE)
Publication Details
- Journal
- Leukemia
- Published
- 2025-05-20
- DOI
- https://doi.org/10.1038/s41375-025-02626-2
- Citations
- 2
- Primary Topic
- Acute Lymphoblastic Leukemia research
- Type
- article
- Field-Weighted Citation Impact
- 3.76
Funders
- Deutsches Zentrum für Infektionsforschung
- Lasten Syöpäsäätiö Väreen
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Jane ja Aatos Erkon Säätiö
- José Carreras Leukämie-Stiftung
- Deutsche Krebshilfe
- Bundesamt für Strahlenschutz
- Deutsche Kinderkrebsstiftung