Dysregulation of PAX5 causes uncommitted B cell development and tumorigenesis in mice

Boast, B.; Helian, K.; Andrews, D.; Li, X.; Cho, V.; Closa Mosquera, A.; Sutton, H. J.; Reed, J. H.; Bergmann, H.; Roots, C. M.; Yabas, M.; Barthel, N.; Omari, S. A.; Young, C.; Miosge, L. A.; Eyras, E.; Nutt, S. L.; Hein, N.; Hannan, K. M.; Cockburn, I. A.; Goodnow, C. C.; Enders, A.

doi:10.1101/2021.01.29.428877

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bioRxiv · 10.1101/2021.01.29.428877

Dysregulation of PAX5 causes uncommitted B cell development and tumorigenesis in mice

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Abstract

PAX5 is the master transcription factor controlling B cell identity. In humans, mutations in PAX5 account for 30% of B cell acute lymphoblastic leukemia (B-ALL) cases. Investigating the causal effects of PAX5 mutations has however been difficult due to the premature lethality of Pax5-/- mice. Here we describe a novel mouse strain with a premature STOP mutation in Pax5 (Y351*) that produces a truncated protein and reduction in protein function, yet still allows for some B cell development to occur. A population of uncommitted and multipotent CD19+B220- B cells develops in the bone marrow of homozygous mice leading to the development of B-ALL. We show that the tumors frequently acquire secondary mutations in Jak3, and Ptpn11 highlighting key pathways interacting with PAX5 during malignant transformation. Analysis of the PAX5Y351* mice provide insight not only into the functional consequence of reduced PAX5 activity on B cell development and identity, but also provides an avenue in which to study PAX5-driven B-ALL in mice. One Sentence SummaryReduction in PAX5 function in mice induces the development of uncommitted B cells that have multipotent and malignant potential.

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Boast, B., Helian, K., Andrews, D., Li, X., Cho, V., Closa Mosquera, A., Sutton, H. J., Reed, J. H., Bergmann, H., Roots, C. M., Yabas, M., Barthel, N., Omari, S. A., Young, C., Miosge, L. A., Eyras, E., Nutt, S. L., Hein, N., Hannan, K. M., Cockburn, I. A., Goodnow, C. C., Enders, A.. 2021-01-31. Dysregulation of PAX5 causes uncommitted B cell development and tumorigenesis in mice. https://doi.org/10.1101/2021.01.29.428877

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