TY  - JOUR
AU  - Auer, Franziska
AU  - Morcos, Mina N F
AU  - Sipola, Mikko
AU  - Akhtar, Irfan
AU  - Moisio, Sanni
AU  - Vogt, Julia
AU  - Haag, Rebecca
AU  - Lahnalampi, Mari
AU  - Tuononen, Tiina J
AU  - Hanel, Andrea
AU  - Viitasalo, Anna
AU  - Friedrich, Ulrike A
AU  - Dahl, Andreas
AU  - Prexler, Carolin
AU  - Pandyra, Aleksandra A
AU  - Stepensky, Polina
AU  - Takagi, Masatoshi
AU  - Borkhardt, Arndt
AU  - Heinäniemi, Merja
AU  - Hauer, Julia
TI  - Trajectories from single-cells to PAX5-driven leukemia reveal PAX5-MYC interplay in vivo.
JO  - Leukemia
VL  - 39
IS  - 7
SN  - 0887-6924
CY  - London
PB  - Springer Nature
M1  - DKFZ-2025-01038
SP  - 1607-1626
PY  - 2025
N1  - 2025 Jul;39(7):1607-1626
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:40394211
DO  - DOI:10.1038/s41375-025-02626-2
UR  - https://inrepo02.dkfz.de/record/301499
ER  -