title: A c-Myc/miR17-92/Pten Axis Controls PI3K-Mediated Positive and Negative Selection in B Cell Development and Reconstitutes CD19 Deficiency.
abstract: PI3K activity determines positive and negative selection of B cells, a key process for immune tolerance and B cell maturation. Activation of PI3K is balanced by phosphatase and tensin homolog (Pten), the PI3K's main antagonistic phosphatase. Yet, the extent of feedback regulation between PI3K activity and Pten expression during B cell development is unclear. Here, we show that PI3K control of this process is achieved post-transcriptionally by an axis composed of a transcription factor (c-Myc), a microRNA (miR17-92), and Pten. Enhancing activation of this axis through overexpression of miR17-92 reconstitutes the impaired PI3K activity for positive selection in CD19-deficient B cells and restores most of the B cell developmental impairments that are evident in CD19-deficient mice. Using a genetic approach of deletion and complementation, we show that the c-Myc/miR17-92/Pten axis critically controls PI3K activity and the sensitivity of immature B cells to negative selection imposed by activation-induced cell death.
authors.affiliation: Department of Immunology, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Benhamou
authors.affiliation: Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Labi
authors.affiliation: Department of Immunology, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Rostislav
authors.initials: R
authors.lastname: Novak
authors.affiliation: Department of Immunology, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dai
authors.affiliation: Department of Immunology, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Shani
authors.initials: S
authors.lastname: Shafir-Alon
authors.affiliation: Department of Immunology, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Ariel
authors.initials: A
authors.lastname: Weiss
authors.affiliation: Department of Immunology, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Renaud
authors.initials: R
authors.lastname: Gaujoux
authors.affiliation: Tumor Immunology Program, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Arnold
authors.affiliation: Department of Immunology, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Shai S
authors.initials: SS
authors.lastname: Shen-Orr
authors.affiliation: Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
authors.affiliation: Department of Immunology, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel. Electronic address: melamedd@tx.technion.ac.il.
authors.forename: Doron
authors.initials: D
authors.lastname: Melamed
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics* / Q000378:metabolism; D001402:B-Lymphocytes / Q000502:physiology*; D016923:Cell Death; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D005816:Genetic Complementation Test; D006579:Heterozygote; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D018941:Antigens, CD19; C000604812:CD19 antigen, mouse; D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; C541873:Mirn92 microRNA, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D019869:Phosphatidylinositol 3-Kinases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D053487:DEAD-box RNA Helicases