Driver mutations in Janus kinases in a mouse model of B-cell leukemia induced by deletion of PU.1 and Spi-B

Blood Adv. 2018 Nov 13;2(21):2798-2810. doi: 10.1182/bloodadvances.2018019950.


Precursor B-cell acute lymphoblastic leukemia (B-ALL) is associated with recurrent mutations that occur in cancer-initiating cells. There is a need to understand how driver mutations influence clonal evolution of leukemia. The E26-transformation-specific (ETS) transcription factors PU.1 and Spi-B (encoded by Spi1 and Spib) execute a critical role in B-cell development and serve as complementary tumor suppressors. Here, we used a mouse model to conditionally delete Spi1 and Spib genes in developing B cells. These mice developed B-ALL with a median time to euthanasia of 18 weeks. We performed RNA and whole-exome sequencing (WES) on leukemias isolated from Mb1-CreΔPB mice and identified single nucleotide variants (SNVs) in Jak1, Jak3, and Ikzf3 genes, resulting in amino acid sequence changes. Jak3 mutations resulted in amino acid substitutions located in the pseudo-kinase (R653H, V670A) and in the kinase (T844M) domains. Introduction of Jak3 T844M into Spi1/Spib-deficient precursor B cells was sufficient to promote proliferation in response to low IL-7 concentrations in culture, and to promote proliferation and leukemia-like disease in transplanted mice. We conclude that mutations in Janus kinases represent secondary drivers of leukemogenesis that cooperate with Spi1/Spib deletion. This mouse model represents a useful tool to study clonal evolution in B-ALL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / transplantation
  • Cell Proliferation
  • Disease Models, Animal
  • Ikaros Transcription Factor
  • Interleukin-7 / pharmacology
  • Janus Kinase 1 / chemistry
  • Janus Kinase 1 / genetics*
  • Janus Kinase 3 / chemistry
  • Janus Kinase 3 / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutagenesis, Site-Directed
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-ets / genetics*
  • Receptors, Interleukin-7 / metabolism
  • Sequence Deletion
  • Trans-Activators / chemistry
  • Trans-Activators / genetics*


  • Ikzf3 protein, mouse
  • Interleukin-7
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ets
  • Receptors, Interleukin-7
  • Spi-B protein, mouse
  • Trans-Activators
  • proto-oncogene protein Spi-1
  • Ikaros Transcription Factor
  • Jak1 protein, mouse
  • Jak3 protein, mouse
  • Janus Kinase 1
  • Janus Kinase 3