期刊
HAEMATOLOGICA
卷 101, 期 4, 页码 417-426出版社
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2015.125336
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资金
- NIH [R21CA162259, P20 MD006988, 2R25 GM060507, R01 HL095120]
- St. Baldrick's Research Grant
- Hyundai Hope on Wheels Scholar Hope Grant
- Department of Pathology and Human Anatomy
- Department of Basic Sciences
- Center for Health Disparities and Molecular Medicine
- Loma Linda University
- St Baldrick's Foundation Career Development Award
- Hyundai Hope on Wheels Scholar Grant Award
- Four Diamonds Fund of the Pennsylvania State University
- John Wawrynovic Leukemia Research Scholar Endowment
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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