PAX5-Inherited susceptibility causes leukemia by conferring sensitivity to DNA damage in preleukemic B cells

We used microarrays to analyze gene expression changes in leukemic bone marrow cells from Pax5+/- and WT mice, comparing them with preleukemic bone marrow precursor B cells from both genotypes. All mice were exposed to a single low-dose irradiation (2 Gy). PAX5 is a master regulator of B-cell development, and germline mutations in PAX5 predispose individuals to B-cell acute lymphoblastic leukemia (B-ALL). While PAX5 alterations are a hallmark of B-ALL, the mechanisms linking inherited susceptibility to leukemic transformation remain poorly understood. Here, we provide in vivo genetic evidence demonstrating that reduced Pax5 dosage increases sensitivity to DNA damage, acting as a key factor in B-ALL initiation. Using a mouse model of Pax5 heterozygosity, we show that exposure to a single low-dose irradiation (2 Gy) significantly accelerates leukemia onset, establishing a direct link between genetic predisposition and environmental stress. Notably, the resulting murine B-ALLs closely resemble the human disease, exhibiting complete Pax5 loss, CD19 downregulation, and a high incidence of DNA double-strand breaks. Mechanistically, we identify Pax5 as a regulator of p53-mediated DNA damage responses in preleukemic B cells, highlighting its role beyond lineage specification. These findings provide a mechanistic framework for the interplay between PAX5 deficiency, genomic instability, and environmental factors in early B-ALL development, uncovering new potential vulnerabilities for therapeutic intervention. Leukemic bone marrow cells from 10 Pax5+/- mice irradiated with 2 Gy. Preleukemic proB and preB cells after 3 weeks of irradiation (2 Gy) from 7 Pax5+/- mice. Leukemic bone marrow cells from 4 wild-type mice irradiated with 2 Gy. Preleukemic proB and preB cells after 3 weeks of irradiation (2 Gy) from 3 wild-type mice.