Journal Article

DKFZ-2025-01038

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Trajectories from single-cells to PAX5-driven leukemia reveal PAX5-MYC interplay in vivo.

Auer, F. ; Morcos, M. N. F. ; Sipola, M. ; Akhtar, I. ; Moisio, S. ; Vogt, J. ; Haag, R. ; Lahnalampi, M. ; Tuononen, T. J. ; Hanel, A. ; Viitasalo, A. ; Friedrich, U. A. ; Dahl, A. ; Prexler, C. ; Pandyra, A. A. ; Stepensky, P. ; Takagi, M. ; Borkhardt, A. ; Heinäniemi, M. ; Hauer, J.DKFZ*

2025
Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41375-025-02626-2

Abstract: 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.

Note: 2025 Jul;39(7):1607-1626

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Contributing Institute(s):

1. DKTK Koordinierungsstelle München (MU01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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