Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 40, Issue 18, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00189-20
Keywords
PU-1; Spi-B; ETS transcription factors; gene regulation; leukemia; reactive oxygen species; transcription factors
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Funding
- Leukemia and Lymphoma Society of Canada [569086]
- Canadian Institutes of Health Research [142250]
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Precursor B cell acute lymphoblastic leukemia (B-ALL) is caused by genetic lesions in developing B cells that function as drivers for the 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-Cre Delta PB). Whole-exome-sequencing analysis revealed recurrent mutations in Jak3 (encoding Janus kinase 3), Jak1, and Ikzf3 (encoding Aiolos). Mutations with a 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 a low VAF, were dominated by C -> A transversions associated with 8-oxoguanine DNA damage caused by reactive oxygen species (ROS). The Janus kinase (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.
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