%0 Journal Article
%A Auer, Franziska
%A Morcos, Mina N F
%A Sipola, Mikko
%A Akhtar, Irfan
%A Moisio, Sanni
%A Vogt, Julia
%A Haag, Rebecca
%A Lahnalampi, Mari
%A Tuononen, Tiina J
%A Hanel, Andrea
%A Viitasalo, Anna
%A Friedrich, Ulrike A
%A Dahl, Andreas
%A Prexler, Carolin
%A Pandyra, Aleksandra A
%A Stepensky, Polina
%A Takagi, Masatoshi
%A Borkhardt, Arndt
%A Heinäniemi, Merja
%A Hauer, Julia
%T Trajectories from single-cells to PAX5-driven leukemia reveal PAX5-MYC interplay in vivo.
%J Leukemia
%V 39
%N 7
%@ 0887-6924
%C London
%I Springer Nature
%M DKFZ-2025-01038
%P 1607-1626
%D 2025
%Z 2025 Jul;39(7):1607-1626
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40394211
%R 10.1038/s41375-025-02626-2
%U https://inrepo02.dkfz.de/record/301499