Pax5 is a tumor suppressor in mouse mutagenesis models of acute lymphoblastic leukemia

To examine the role of PAX5 alterations in leukemogenesis, we performed mutagenesis screens of mice heterozygous for a loss-of-function Pax5 allele. Both chemical and retroviral mutagenesis resulted in a significantly increased penetrance and reduced latency of leukemia, with a shift to B-lymphoid lineage. We observed a range of maturation of lymphoid tumors, and genomic profiling identified a high frequency of secondary genomic mutations, deletions and retroviral insertions targeting B-lymphoid development, including Pax5, and additional genes and pathways known to be mutated in ALL, including tumor suppressors, Ras and JAK-STAT signaling. These results support the notion that loss-of-function of PAX5 is a central event in leukemogenesis and contributes to the arrest in lymphoid maturation characteristic of this disease. Moreover, we validate the role of mutations in additional pathways and demonstrate that sequential acquisition of genetic alterations is required for establishment of leukemia. Mice haploinsufficient for PAX5 were analyzed