title: Thymic stromal-derived lymphopoietin induces proliferation of pre-B leukemia and antagonizes mTOR inhibitors, suggesting a role for interleukin-7Ralpha signaling.
abstract: Understanding the pathogenesis of leukemia in the context of lymphopoiesis may reveal novel therapeutic targets. Previously, we have shown that mTOR inhibitors (MTI) show activity in vitro and in preclinical models of both human and murine precursor B acute lymphoblastic leukemia (pre-B ALL), inhibiting cell proliferation and inducing apoptosis. These MTI-mediated effects can be reversed by interleukin-7 (IL-7), an important regulator of early B-cell development. This observation led us to examine the contribution of signaling via the IL-7Ralpha chain, which is shared by the receptor complexes of IL-7 and thymic stromal-derived lymphopoietin (TSLP). TSLP is closely related to IL-7 and active in lymphopoiesis, but an effect of TSLP on leukemia cells has not been described. We examined the effect of TSLP on pre-B ALL cells and their response to MTIs. Here, we show that TSLP stimulates proliferation of pre-B ALL cell lines. TSLP also partially reverses the effects of MTI on proliferation, apoptosis, and ribosomal protein S6 and 4E-BP1 phosphorylation in cell lines, with similar biological effects seen in some primary human lymphoblast samples. These data show that TSLP can promote survival of pre-B ALL cells and antagonize the effects of MTIs. These findings suggest that IL-7Ralpha chain is responsible for transducing the survival signal that overcomes MTI-mediated growth inhibition in pre-B ALL. Thus, further exploration of the IL-7Ralpha pathway may identify potential therapeutic targets in the treatment of ALL. Our data illustrate that growth-factor-mediated signaling may provide one mechanism of MTI resistance.
authors.affiliation: Division of Oncology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, and Department of Pediatrics, Division of Hematology and Oncology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
authors.forename: Valerie I
authors.initials: VI
authors.lastname: Brown
authors.forename: Jessica
authors.initials: J
authors.lastname: Hulitt
authors.forename: Jonathan
authors.initials: J
authors.lastname: Fish
authors.forename: Cecilia
authors.initials: C
authors.lastname: Sheen
authors.forename: Marlo
authors.initials: M
authors.lastname: Bruno
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.forename: Martin
authors.initials: M
authors.lastname: Carroll
authors.forename: Junjie
authors.initials: J
authors.lastname: Fang
authors.forename: David
authors.initials: D
authors.lastname: Teachey
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D039642:Eukaryotic Initiation Factors; D006801:Humans; D015851:Interleukin-7 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D053699:Interleukin-7 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000378:metabolism; D053616:Janus Kinase 3 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D038601:Ribosomal Protein S6 / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016207:Cytokines; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D038601:Ribosomal Protein S6; D050799:STAT5 Transcription Factor; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D053613:Janus Kinase 1; D053616:Janus Kinase 3; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D000094632:Thymic Stromal Lymphopoietin