Dysregulation of PAX5 causes uncommitted B cell development and tumorigenesis in mice
Adria Closa Mosquera,
Henry J Sutton,
Joanne H Reed,
Carla M Roots,
Lisa A Miosge,
Stephen L Nutt,
Katherine M Hannan,
Ian A Cockburn,
Posted 31 Jan 2021
bioRxiv DOI: 10.1101/2021.01.29.428877
Posted 31 Jan 2021
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.
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