A novel xenograft model to study the role of TSLP-induced CRLF2 signals in normal and malignant human B lymphopoiesis
Olivia L. Francis,
Terry-Ann M. Milford,
Shannalee R. Martinez,
Ineavely Baez,
Jacqueline S. Coats,
Karina Mayagoitia,
Katherine R. Concepcion,
Elizabeth Ginelli,
Cornelia Beldiman,
Abigail Benitez,
Abby J. Weldon,
Keshav Arogyaswamy,
Parveen Shiraz,
Ross Fisher,
Christopher L. Morris,
Xiao-Bing Zhang,
Valeri Filippov,
Ben Van Handel,
Zheng Ge,
Chunhua Song,
Sinisa Dovat,
Ruijun Jeanna Su,
Kimberly J. Payne
Affiliations
Olivia L. Francis
Loma Linda University, CA, USA
Terry-Ann M. Milford
Loma Linda University, CA, USA
Shannalee R. Martinez
Loma Linda University, CA, USA
Ineavely Baez
Loma Linda University, CA, USA
Jacqueline S. Coats
Loma Linda University, CA, USA
Karina Mayagoitia
Loma Linda University, CA, USA
Katherine R. Concepcion
Loma Linda University, CA, USA
Elizabeth Ginelli
Loma Linda University, CA, USA
Cornelia Beldiman
Loma Linda University, CA, USA
Abigail Benitez
Loma Linda University, CA, USA
Abby J. Weldon
Loma Linda University, CA, USA
Keshav Arogyaswamy
Loma Linda University, CA, USA
Parveen Shiraz
Loma Linda University, CA, USA
Ross Fisher
Loma Linda University, CA, USA
Christopher L. Morris
Loma Linda University, CA, USA
Xiao-Bing Zhang
Loma Linda University, CA, USA
Valeri Filippov
Loma Linda University, CA, USA
Ben Van Handel
Novogenix Laboratories, LLC, 1425 San Pablo, CA, USA
Zheng Ge
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
Chunhua Song
Pennsylvania State University Medical College, Department of Pediatrics, Hershey, PA, USA
Sinisa Dovat
Pennsylvania State University Medical College, Department of Pediatrics, Hershey, PA, USA
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.
