| First Author | Christie DA | Year | 2015 |
| Journal | J Immunol | Volume | 194 |
| Issue | 2 | Pages | 595-605 |
| PubMed ID | 25505273 | Mgi Jnum | J:280596 |
| Mgi Id | MGI:6363397 | Doi | 10.4049/jimmunol.1401569 |
| Citation | Christie DA, et al. (2015) PU.1 opposes IL-7-dependent proliferation of developing B cells with involvement of the direct target gene bruton tyrosine kinase. J Immunol 194(2):595-605 |
| abstractText | Deletion of genes encoding the E26 transformation-specific transcription factors PU.1 and Spi-B in B cells (CD19-CreDeltaPB 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-CreDeltaPB mice. Enriched pro-B cells from CD19-CreDeltaPB mice induced disease upon transplantation, suggesting that these were leukemia-initiating cells. Bone marrow cells from preleukemic CD19-CreDeltaPB 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-CreDeltaPB cells compared with controls. Induction of PU.1 expression in cultured CD19-CreDeltaPB 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. |
