1. Janus Kinase Mutations in Mice Lacking PU.1 and Spi-B Drive B Cell Leukemia through Reactive Oxygen Species-Induced DNA Damage
- Author
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Mariano Avino, Jacob Ferguson, James Iansavitchous, Danish Mahmood, Kurt Clemmer, Michelle Lim, Carolina R. Batista, Rachel Creighton, Rodney P. DeKoter, Bruno R de Oliveira, and Devon Knight
- Subjects
Male ,DNA damage ,Biology ,Somatic evolution in cancer ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,Proto-Oncogene Proteins ,medicine ,Transcription factors ,Leukemia, B-Cell ,Animals ,Humans ,Molecular Biology ,030304 developmental biology ,Cell Proliferation ,Mice, Knockout ,0303 health sciences ,B-Lymphocytes ,Leukemia ,Transition (genetics) ,Proto-Oncogene Proteins c-ets ,Janus kinase 3 ,PU.1 ,Janus Kinase 3 ,Cell Biology ,Cytidine deaminase ,Janus Kinase 1 ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Spi-B ,Molecular biology ,Gene regulation ,Mice, Inbred C57BL ,030220 oncology & carcinogenesis ,B-cell leukemia ,Mutation ,Trans-Activators ,ETS transcription factors ,Janus kinase ,Reactive oxygen species ,Reactive Oxygen Species ,DNA Damage ,Research Article - Abstract
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-CreΔPB). 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.
- Published
- 2020