title: A novel xenograft model to study the role of TSLP-induced CRLF2 signals in normal and malignant human B lymphopoiesis.
abstract: Thymic stromal lymphopoietin (TSLP) stimulates in-vitro proliferation of human fetal B-cell precursors. However, its in-vivo role during normal human B lymphopoiesis is unknown. Genetic alterations that cause overexpression of its receptor component, cytokine receptor-like factor 2 (CRLF2), lead to high-risk B-cell acute lymphoblastic leukemia implicating this signaling pathway in leukemogenesis. We show that mouse thymic stromal lymphopoietin does not stimulate the downstream pathways (JAK/STAT5 and PI3K/AKT/mTOR) activated by the human cytokine in primary high-risk leukemia with overexpression of the receptor component. Thus, the utility of classic patient-derived xenografts for in-vivo studies of this pathway is limited. We engineered xenograft mice to produce human thymic stromal lymphopoietin (+T mice) by injection with stromal cells transduced to express the cytokine. Control (-T) mice were produced using stroma transduced with control vector. Normal levels of human thymic stromal lymphopoietin were achieved in sera of +T mice, but were undetectable in -T mice. Patient-derived xenografts generated from +T as compared to -T mice showed a 3-6-fold increase in normal human B-cell precursors that was maintained through later stages of B-cell development. Gene expression profiles in high-risk B-cell acute lymphoblastic leukemia expanded in +T mice indicate increased mTOR pathway activation and are more similar to the original patient sample than those from -T mice. +T/-T xenografts provide a novel pre-clinical model for understanding this pathway in B lymphopoiesis and identifying treatments for high-risk B-cell acute lymphoblastic leukemia with overexpression of cytokine-like factor receptor 2.
authors.affiliation: Loma Linda University, CA, USA.
authors.forename: Olivia L
authors.initials: OL
authors.lastname: Francis
authors.affiliation: Loma Linda University, CA, USA.
authors.forename: Terry-Ann M
authors.initials: TA
authors.lastname: Milford
authors.affiliation: Loma Linda University, CA, USA.
authors.forename: Shannalee R
authors.initials: SR
authors.lastname: Martinez
authors.affiliation: Loma Linda University, CA, USA.
authors.forename: Ineavely
authors.initials: I
authors.lastname: Baez
authors.affiliation: Loma Linda University, CA, USA.
authors.forename: Jacqueline S
authors.initials: JS
authors.lastname: Coats
authors.affiliation: Loma Linda University, CA, USA.
authors.forename: Karina
authors.initials: K
authors.lastname: Mayagoitia
authors.affiliation: Loma Linda University, CA, USA.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Concepcion
authors.affiliation: Loma Linda University, CA, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ginelli
authors.affiliation: Loma Linda University, CA, USA.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Beldiman
authors.affiliation: Loma Linda University, CA, USA.
authors.forename: Abigail
authors.initials: A
authors.lastname: Benitez
authors.affiliation: Loma Linda University, CA, USA.
authors.forename: Abby J
authors.initials: AJ
authors.lastname: Weldon
authors.affiliation: Loma Linda University, CA, USA.
authors.forename: Keshav
authors.initials: K
authors.lastname: Arogyaswamy
authors.affiliation: Loma Linda University, CA, USA.
authors.forename: Parveen
authors.initials: P
authors.lastname: Shiraz
authors.affiliation: Loma Linda University, CA, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Fisher
authors.affiliation: Loma Linda University, CA, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Morris
authors.affiliation: Loma Linda University, CA, USA.
authors.forename: Xiao-Bing
authors.initials: XB
authors.lastname: Zhang
authors.affiliation: Loma Linda University, CA, USA.
authors.forename: Valeri
authors.initials: V
authors.lastname: Filippov
authors.affiliation: Novogenix Laboratories, LLC, 1425 San Pablo, CA, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Van Handel
authors.affiliation: The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Department of Hematology, Nanjing 210029, China Pennsylvania State University Medical College, Department of Pediatrics, Hershey, PA, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Ge
authors.affiliation: Pennsylvania State University Medical College, Department of Pediatrics, Hershey, PA, USA.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Song
authors.affiliation: Pennsylvania State University Medical College, Department of Pediatrics, Hershey, PA, USA.
authors.forename: Sinisa
authors.initials: S
authors.lastname: Dovat
authors.affiliation: Loma Linda University, CA, USA.
authors.forename: Ruijun Jeanna
authors.initials: RJ
authors.lastname: Su
authors.affiliation: Loma Linda University, CA, USA kpayne@llu.edu.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Payne
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D064593:Heterografts / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D018655:Lymphocyte Count; D038041:Lymphopoiesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D019076:Transgenes; D014183:Transplantation, Heterologous
chemical_list: D053613:Janus Kinase 1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018121:Receptors, Cytokine; D019893:Ribosomal Protein S6 Kinases; D050799:STAT5 Transcription Factor; D058570:TOR Serine-Threonine Kinases; C498762:CRLF2 protein, human; C546843:mTOR protein, mouse; C507905:Jak1 protein, mouse