Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7-driven B lymphopoiesis

Hu Zeng, Mei Yu, Haiyan Tan, Yuxin Li, Wei Su, Hao Shi, Yogesh Dhungana, Cliff Guy, Geoffrey Neale, Caryn Cloer, Junmin Peng, Demin Wang, Hongbo Chi

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7 Scopus citations

Abstract

Interleukin-7 (IL-7) drives early B lymphopoiesis, but the underlying molecular circuits remain poorly understood, especially how Stat5 (signal transducer and activator of transcription 5)-dependent and Stat5- independent pathways contribute to this process. Combining transcriptome and proteome analyses and mouse genetic models, we show that IL-7 promotes anabolic metabolism and biosynthetic programs in pro-B cells. IL- 7-mediated activation of mTORC1 (mechanistic target of rapamycin complex 1) supported cell proliferation and metabolism in a Stat5-independent, Myc-dependent manner but was largely dispensable for cell survival or Rag1 and Rag2 gene expression. mTORC1 was also required for Myc-driven lymphomagenesis. PI3K (phosphatidylinositol 3-kinase) and mTORC1 had discrete effects on Stat5 signaling and independently controlled B cell development. PI3K was actively suppressed by PTEN (phosphatase and tensin homolog) in pro-B cells to ensure proper IL-7R expression, Stat5 activation, heavy chain rearrangement, and cell survival, suggesting the unexpected bifurcation of the classical PI3K-mTOR signaling. Together, our integrative analyses establish IL-7R-mTORC1-Myc and PTEN-mediated PI3K suppression as discrete signaling axes driving B cell development, with differential effects on IL-7R-Stat5 signaling.

Original languageEnglish (US)
Article numbereaar5701
JournalScience advances
Volume4
Issue number1
DOIs
StatePublished - Jan 1 2018

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Zeng, H., Yu, M., Tan, H., Li, Y., Su, W., Shi, H., Dhungana, Y., Guy, C., Neale, G., Cloer, C., Peng, J., Wang, D., & Chi, H. (2018). Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7-driven B lymphopoiesis. Science advances, 4(1), [eaar5701]. https://doi.org/10.1126/sciadv.aar5701