Master of Science
Microbiology and Immunology
DeKoter, Rodney P.
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.
Summary for Lay Audience
B cell acute lymphoblastic leukemia (B-ALL) is the second leading cause of death by cancer in children. This disease is associated with recurrent mutations in genes that encode transcription factors driving B cell development, such as SpiB and PU.1. We previously showed that deletion of both SpiB and PU.1 leads to 100% incidence of B-ALL in mice. However, the mice take 18 weeks to develop leukemia. Thus, we hypothesized that additional cooperating mutations are necessary for the development of B-ALL in mice. Using next-generation sequencing on mouse tumors, we determined that all mice had recurrent mutations in Jak genes. Analysis of the mutation patterns suggested that the mutations arose from overexpression of Aicda which led to reactive oxygen species-induced DNA damage. Treatment of mice with Ruxolitinib, a JAK inhibitor, doubled survival and delayed tumor growth. In conclusion, we have shown that Jaks are causal mutations and tumour progression can be delayed through JAK inhibition.
Lim, Michelle, "B Cell Acute Lymphoblastic Leukemia is Driven by Activating Janus Kinase Mutations Cooperating with Spi1 and Spib Deletions in a Murine Model" (2020). Electronic Thesis and Dissertation Repository. 7019.
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Available for download on Friday, May 20, 2022