Cho, V. | Search bioRxiv

bioRxiv2021

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

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.

immunology↗

bioRxiv2019

Absence of pathogenic Short Tandem Repeat expansions in Systemic Lupus Erythematosus disease-associated genes

Short tandem repeat (STR) expansions have been shown to be pathogenic in human neurological diseases, such as Huntington disease. Yet, the potential role of STRs in non-neurological diseases has yet to be fully investigated. In this study, the potential role of STR expansions in the pathogenesis of systemic lupus erythematosus (SLE) was investigated using patient genomic data and two computational tools, HipSTR and exSTRa. The length variability of STRs in 76 SLE-associated genes was compared using exome data from 271 SLE affected individuals and 158 of their unaffected relatives. We conclude that no large STR expansions associated with SLE were present in these affected individuals within the 76 genes investigated. Lack of evidence does not negate a pathogenic role for STR expansions in SLE, yet given the number of individuals included in this study, we expect that this is not a common source of pathogenesis in SLE.\n\nSignificance statementThe increasing availability and decreasing cost of sequencing genomes lends itself to computational analysis, extracting information to aid diagnosis, guide treatment or discover disease mechanisms and new treatments. Computational tools have been developed to look for various types of mutations, including short tandem repeats (STRs), which has been shown to cause diseases such as Huntington disease. Limited research on the possible role of STR expansions in systemic lupus erythematosus (SLE) has been done. Here we use computational tools to compare the length of STRs in 76 SLE-associated genes in patients and their unaffected relatives. Our results did not identify any large STR expansions associated with SLE, and further research is required to gain a better understanding of this complex disease.

genomics↗