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 SongSinisa Dovat, Ruijun Jeanna Su, Kimberly J. Payne

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)417-426
Number of pages10
JournalHaematologica
Volume101
Issue number4
DOIs
StatePublished - Mar 31 2016

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Lymphopoiesis
Cytokine Receptors
Heterografts
B-Lymphocytes
Precursor Cell Lymphoblastic Leukemia-Lymphoma
B-Lymphoid Precursor Cells
Cytokines
Stromal Cells
thymic stromal lymphopoietin
Phosphatidylinositol 3-Kinases
Transcriptome
Leukemia
Injections
Serum

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

Francis, O. L., Milford, T. A. M., Martinez, S. R., Baez, I., Coats, J. S., Mayagoitia, K., ... Payne, K. J. (2016). A novel xenograft model to study the role of TSLP-induced CRLF2 signals in normal and malignant human B lymphopoiesis. Haematologica, 101(4), 417-426. https://doi.org/10.3324/haematol.2015.125336
Francis, Olivia L. ; Milford, Terry Ann M. ; Martinez, Shannalee R. ; Baez, Ineavely ; Coats, Jacqueline S. ; Mayagoitia, Karina ; Concepcion, Katherine R. ; Ginelli, Elizabeth ; Beldiman, Cornelia ; Benitez, Abigail ; Weldon, Abby J. ; Arogyaswamy, Keshav ; Shiraz, Parveen ; Fisher, Ross ; Morris, Christopher L. ; Zhang, Xiao Bing ; Filippov, Valeri ; van Handel, Ben ; Ge, Zheng ; Song, Chunhua ; Dovat, Sinisa ; Su, Ruijun Jeanna ; Payne, Kimberly J. / A novel xenograft model to study the role of TSLP-induced CRLF2 signals in normal and malignant human B lymphopoiesis. In: Haematologica. 2016 ; Vol. 101, No. 4. pp. 417-426.
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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.",
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Francis, OL, Milford, TAM, Martinez, SR, Baez, I, Coats, JS, Mayagoitia, K, Concepcion, KR, Ginelli, E, Beldiman, C, Benitez, A, Weldon, AJ, Arogyaswamy, K, Shiraz, P, Fisher, R, Morris, CL, Zhang, XB, Filippov, V, van Handel, B, Ge, Z, Song, C, Dovat, S, Su, RJ & Payne, KJ 2016, 'A novel xenograft model to study the role of TSLP-induced CRLF2 signals in normal and malignant human B lymphopoiesis', Haematologica, vol. 101, no. 4, pp. 417-426. https://doi.org/10.3324/haematol.2015.125336

A novel xenograft model to study the role of TSLP-induced CRLF2 signals in normal and malignant human B lymphopoiesis. / Francis, Olivia L.; Milford, Terry Ann M.; Martinez, Shannalee R.; Baez, Ineavely; Coats, Jacqueline S.; Mayagoitia, Karina; Concepcion, Katherine R.; Ginelli, Elizabeth; Beldiman, Cornelia; Benitez, Abigail; Weldon, Abby J.; Arogyaswamy, Keshav; Shiraz, Parveen; Fisher, Ross; Morris, Christopher L.; Zhang, Xiao Bing; Filippov, Valeri; van Handel, Ben; Ge, Zheng; Song, Chunhua; Dovat, Sinisa; Su, Ruijun Jeanna; Payne, Kimberly J.

In: Haematologica, Vol. 101, No. 4, 31.03.2016, p. 417-426.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A novel xenograft model to study the role of TSLP-induced CRLF2 signals in normal and malignant human B lymphopoiesis

AU - Francis, Olivia L.

AU - Milford, Terry Ann M.

AU - Martinez, Shannalee R.

AU - Baez, Ineavely

AU - Coats, Jacqueline S.

AU - Mayagoitia, Karina

AU - Concepcion, Katherine R.

AU - Ginelli, Elizabeth

AU - Beldiman, Cornelia

AU - Benitez, Abigail

AU - Weldon, Abby J.

AU - Arogyaswamy, Keshav

AU - Shiraz, Parveen

AU - Fisher, Ross

AU - Morris, Christopher L.

AU - Zhang, Xiao Bing

AU - Filippov, Valeri

AU - van Handel, Ben

AU - Ge, Zheng

AU - Song, Chunhua

AU - Dovat, Sinisa

AU - Su, Ruijun Jeanna

AU - Payne, Kimberly J.

PY - 2016/3/31

Y1 - 2016/3/31

N2 - 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.

AB - 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.

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