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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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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STAT5 Transcription Factor
Lymphopoiesis
Interleukin-7
Phosphoric Monoester Hydrolases
Phosphatidylinositol 3-Kinase
B-Lymphoid Precursor Cells
Cell Survival
B-Lymphocytes
Genetic Models
Gene Expression Profiling
Proteome
Transcriptional Activation
mechanistic target of rapamycin complex 1
Tensins
Cell Proliferation
Gene Expression

ASJC Scopus subject areas

  • General

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Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7-driven B lymphopoiesis. / Zeng, Hu; Yu, Mei; Tan, Haiyan; Li, Yuxin; Su, Wei; Shi, Hao; Dhungana, Yogesh; Guy, Cliff; Neale, Geoffrey; Cloer, Caryn; Peng, Junmin; Wang, Demin; Chi, Hongbo.

In: Science advances, Vol. 4, No. 1, eaar5701, 01.01.2018.

Research output: Contribution to journalArticle

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, vol. 4, no. 1, eaar5701. https://doi.org/10.1126/sciadv.aar5701
Zeng, Hu ; Yu, Mei ; Tan, Haiyan ; Li, Yuxin ; Su, Wei ; Shi, Hao ; Dhungana, Yogesh ; Guy, Cliff ; Neale, Geoffrey ; Cloer, Caryn ; Peng, Junmin ; Wang, Demin ; Chi, Hongbo. / Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7-driven B lymphopoiesis. In: Science advances. 2018 ; Vol. 4, No. 1.
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AU - Guy, Cliff

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