B Cell Acute Lymphoblastic Leukemia is Driven by Activating Janus Kinase Mutations Cooperating with Spi1 and Spib Deletions in a Murine Model
Abstract
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 and their mechanism(s) of arising in a mouse model of B-ALL driven by PU.1/Spi-B deletion (Mb1-CreDPB). Whole exome sequencing revealed recurrent mutations in Jak3 (encoding Janus Kinase 3) and Jak1. Mutations with high variant allele frequency (VAF) were dominated by C->T transition mutations that were compatible with AID, 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 mutational signatures. These results indicate a reduction in ROS-induced DNA damage, revealing that JAK mutations can alter the course of leukemia clonal evolution through ROS-induced DNA damage.