PAX5 familial Arg38His variant acts as a hypomorphic variant altering the expression of PAX5 targets and can predispose to BCP-ALL in mice.
Leukemic progression in individuals with germline PAX5 mutations requires an additional somatic PAX5 mutation and CDKN2A/B loss.
In recent years, through whole genome analyses, convincing evidence for the contribution of genetic predisposition to childhood B-cell precursor - acute lymphoblastic leukemia (BCP-ALL) due to altered PAX5 has been provided. A recurrent mutation p.Gly183Ser affecting the octapeptide domain has been described in three unrelated families and a p.Arg38His mutation affecting the DNA-binding paired domain reported in another one. We strengthen here the assumption of the inherited character of familial BCP-ALL by identifying the PAX5 p.Arg38His mutation in a family in which the three children developed BCP-ALL. One relapsed two years after his initial diagnosis and was allografted with his brother's cells before the latter developed BCP-ALL. The patient allografted relapsed later from donor-related cells. By syngeneic transplantations in mice, we showed that p.Arg38His expression does not abrogate the engraftment capacity of transduced Pax5-/- pro-B cells unlike wild type PAX5-rescued Pax5-/- pro-B cells and can predispose to BCP-ALL. Through functional and molecular analyses, we demonstrated that p.Arg38His acts as a hypomorphic variant altering the pattern of expression of PAX5 target genes. Our data highlight the importance of transcriptional deregulation, particularly of genes involved in B cell differentiation in familial BCP-ALL. We demonstrated that inherited genetic basis of susceptibility to BCP-ALL has been underestimated and should be considered before any familial allograft.