Janus Kinase mutations in mice lacking PU.1 and Spi-B drive B cell leukemia through reactive oxygen species-induced DNA damage.

Precursor B cell acute lymphoblastic leukemia (B-ALL) is caused by genetic lesions in developing B cells that function as drivers for accumulation of additional mutations in an evolutionary selection process. We investigated secondary drivers of leukemogenesis in a mouse model of B-ALL driven by PU.1/Spi-B deletion (Mb1-CreΔPB). Whole exome sequencing analysis revealed recurrent mutations in Jak3 (encoding Janus Kinase 3), Jak1, and Ikzf3 (encoding Aiolos). Mutations with high variant allele frequency (VAF) were dominated by C->T transition mutations that were compatible with Activation-induced Cytidine Deaminase, whereas the majority of mutations, with low VAF, were dominated by C->A transversions associated with 8-oxoguanine DNA damage caused by reactive oxygen species (ROS). The JAK inhibitor Ruxolitinib delayed leukemia onset, reduced ROS and ROS-induced gene expression signatures, and altered ROS-induced mutational signatures. These results reveal that JAK mutations can alter the course of leukemia clonal evolution through ROS-induced DNA damage.