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

• Published in: Blood advances Vol. 2; no. 21; pp. 2798 - 2810
• Main Authors: Batista, Carolina R., Lim, Michelle, Laramée, Anne-Sophie, Abu-Sardanah, Faisal, Xu, Li S., Hossain, Rajon, Bell, Gillian I., Hess, David A., DeKoter, Rodney P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.11.2018; American Society of Hematology
• Subjects: Lymphoid Neoplasia
• ISSN: 2473-9529; 2473-9537
• 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. •Deletion of genes encoding PU.1 and Spi-B in mice results in precursor B-ALL at 100% incidence.•Genomic analysis reveals mutations in Janus kinase genes that confer growth advantages to B cells in cooperation with Spi1/Spib deletion. [Display omitted]