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Article
PU.1 opposes IL-7-dependent proliferation of developing b cells with involvement of the direct target gene bruton tyrosine kinase
Journal of Immunology
  • Darah A. Christie, Schulich School of Medicine & Dentistry
  • Li S. Xu, Schulich School of Medicine & Dentistry
  • Shereen A. Turkistany, Schulich School of Medicine & Dentistry
  • Lauren A. Solomon, Schulich School of Medicine & Dentistry
  • Stephen K.H. Li, Schulich School of Medicine & Dentistry
  • Edmund Yim, Schulich School of Medicine & Dentistry
  • Ian Welch, Western University
  • Gillian I. Bell, Robarts Research Institute
  • David A. Hess, Robarts Research Institute
  • Rodney P. DeKoter, Schulich School of Medicine & Dentistry
Document Type
Article
Publication Date
1-1-2015
URL with Digital Object Identifier
10.4049/jimmunol.1401569
Abstract

Deletion of genes encoding the E26 transformation-specific transcription factors PU.1 and Spi-B in B cells (CD19-CreΔPB mice) leads to impaired B cell development, followed by B cell acute lymphoblastic leukemia at 100% incidence and with a median survival of 21 wk. However, little is known about the target genes that explain leukemogenesis in these mice. In this study we found that immature B cells were altered in frequency in the bone marrow of preleukemic CD19-CreΔPB mice. Enriched pro-B cells from CD19-CreDPB mice induced disease upon transplantation, suggesting that these were leukemia-initiating cells. Bone marrow cells from preleukemic CD19-CreΔPB mice had increased responsiveness to IL-7 and could proliferate indefinitely in response to this cytokine. Bruton tyrosine kinase (BTK), a negative regulator of IL-7 signaling, was reduced in preleukemic and leukemic CD19-CreΔPB cells compared with controls. Induction of PU.1 expression in cultured CD19-CreΔPB pro-B cell lines induced Btk expression, followed by reduced STAT5 phosphorylation and early apoptosis. PU.1 and Spi-B regulated Btk directly as shown by chromatin immunoprecipitation analysis. Ectopic expression of BTK was sufficient to induce apoptosis in cultured pro-B cells. In summary, these results suggest that PU.1 and Spi-B activate Btk to oppose IL-7 responsiveness in developing B cells.

Citation Information
Darah A. Christie, Li S. Xu, Shereen A. Turkistany, Lauren A. Solomon, et al.. "PU.1 opposes IL-7-dependent proliferation of developing b cells with involvement of the direct target gene bruton tyrosine kinase" Journal of Immunology Vol. 194 Iss. 2 (2015) p. 595 - 605
Available at: http://works.bepress.com/rodney-dekoter/6/