title: Interleukin-7 signaling in human B cell precursor acute lymphoblastic leukemia cells and murine BAF3 cells involves activation of STAT1 and STAT5 mediated via the interleukin-7 receptor alpha chain.
abstract: Interleukin-7 (IL-7) stimulates the proliferation of normal and leukemic B and T cell precursors and T lymphocytes. Activation of the JAK/STAT pathway has been implicated in IL-7R signaling. We investigated which STAT complexes are formed upon stimulation of B cell precursor acute lymphoblastic leukemia (BCP-ALL) cells with IL-7. Gel retardation assays with STAT-binding oligonucleotides showed that IL-7 induces the formation of two major STAT complexes in BCP-ALL cells. Supershifts with anti-STAT antibodies identified these as STAT1 and STAT5 complexes. This pattern of STAT activation was seen in all BCP-ALL cases that respond to IL-7 in proliferation assays. IL-7 also induced STAT/DNA binding in BCP-ALL cases that failed to proliferate in response to IL-7, suggesting that the ability of IL-7R to activate the JAK/STAT pathway per se is not sufficient for proliferation induction. To determine the contribution of the cytoplasmic domain of the IL-7 receptor alpha chain (IL-7R alpha) to activation of STAT proteins, transfectants of the murine pro-B cell line BAF3 were made that express chimeric receptors consisting of the extracellular domain of human granulocyte colony-stimulating factor receptor (G-CSF-R) and the transmembrane and intracellular domains of human IL-7R alpha. Activation of the chimeric G-CSF-R/IL-7R alpha with G-CSF resulted in a full proliferative response and induced the phosphorylation of JAK1 but not JAK2. Major STAT complexes activated by G-CSF-R/IL-7R alpha contained STAT1 or STAT5, while some formation of STAT3-containing complexes was also seen. These findings establish that STAT1 and STAT5, and possibly STAT3, are activated upon stimulation of precursor B cells with IL-7. The data further indicate that the IL-7R alpha chains are directly involved in the activation of JAKs and STATs and have a major role in proliferative signaling in precursor B cells.
authors.affiliation: Department of Hematology, Dr Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
authors.forename: D C
authors.initials: DC
authors.lastname: van der Plas
authors.forename: F
authors.initials: F
authors.lastname: Smiers
authors.forename: K
authors.initials: K
authors.lastname: Pouwels
authors.forename: L H
authors.initials: LH
authors.lastname: Hoefsloot
authors.forename: B
authors.initials: B
authors.lastname: Löwenberg
authors.forename: I P
authors.initials: IP
authors.lastname: Touw
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D001483:Base Sequence; D002051:Burkitt Lymphoma / Q000276:immunology / Q000503:physiopathology; D002460:Cell Line; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D015851:Interleukin-7 / Q000494:pharmacology*; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D007700:Kinetics; D046911:Macromolecular Substances; D051379:Mice; D008894:Milk Proteins; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000503:physiopathology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D020395:Receptors, Interleukin-7; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D013936:Thymidine / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D017931:DNA Primers; D004268:DNA-Binding Proteins; D015851:Interleukin-7; D046911:Macromolecular Substances; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D018123:Receptors, Interleukin; D020395:Receptors, Interleukin-7; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050799:STAT5 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D013936:Thymidine