Janus Kinase Mutations in Mice Lacking PU.1 and Spi-B Drive B Cell Leukemia through Reactive Oxygen Species-Induced DNA Damage

Mol Cell Biol. 2020 Aug 28;40(18):e00189-20. doi: 10.1128/MCB.00189-20. Print 2020 Aug 28.


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.

Keywords: ETS transcription factors; PU.1; Spi-B; gene regulation; leukemia; reactive oxygen species; transcription factors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA Damage*
  • Humans
  • Janus Kinase 1 / genetics*
  • Janus Kinase 1 / metabolism*
  • Janus Kinase 3 / metabolism
  • Leukemia, B-Cell / genetics
  • Leukemia, B-Cell / metabolism*
  • Leukemia, B-Cell / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-ets / genetics
  • Proto-Oncogene Proteins c-ets / metabolism
  • Reactive Oxygen Species / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism


  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ets
  • Reactive Oxygen Species
  • Spi-B protein, mouse
  • Trans-Activators
  • proto-oncogene protein Spi-1
  • JAK1 protein, human
  • JAK3 protein, human
  • Janus Kinase 1
  • Janus Kinase 3

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