Xenograft Model to Study Impact of CRLF2-Ligand in Hispanic Childhood B-ALL

研究 CRLF2 配体对西班牙裔儿童 B-ALL 影响的异种移植模型

• 批准号: 8478068
• 负责人: KIMBERLY J PAYNE
• 金额: $ 15.18万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8478068
• 关键词: American; Animal Model; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Biological Models; Bone Marrow; Bone Marrow Diseases; Cells; Cessation of life; Characteristics; Child; Childhood; Chimerism; Complex; Cytokine Receptors; Cytometry; Data; Death Rate; Defect; Development; Disease Progression; Engineering; Engraftment; Environment; Ethnic Origin; Euthanasia; Evaluation; Event; Flow Cytometry; Frequencies; Goals; Growth Factor Receptors; Harvest; Hispanics; Human; Immune; Immunodeficient Mouse; Interleukin-7; Latino; Lead; Lesion; Leukemic Cell; Ligands; Ligation; Malignant - descriptor; Marrow; Mediating; Modeling; Molecular; Mus; Mutation; Normal Range; Pediatric Hematology/Oncology; Phosphorylation; Play; Proteins; Receptor Activation; Receptor Signaling; Relapse; Reporting; Role; STAT5A gene; Serum; Signal Transduction; Societies; Source; Species Specificity; TSLP gene; Testing; Time; Transplantation; Work; Xenograft Model; alpha chain interleukin-7 receptor; cell stroma; cytokine; health disparity; high risk; in vivo; in vivo Model; leukemia; mTOR Inhibitor; meetings; novel therapeutic intervention; outcome forecast; overexpression; peripheral blood; receptor; therapeutic target; tumor microenvironment; vector

DESCRIPTION (provided by applicant): Hispanic children have a 39% higher death rate due to ALL than white children. A major cause of this health disparity in survival is the lack of therapies that specifically target the high-risk B-ALL caused by deregulated CRLF2 (CRLF2-d). Genetic defects resulting in B cells that overexpress the cytokine receptor component, CRLF2, lead to malignant transformation and high-risk CRLF2-d B-ALL with poor prognosis. B-ALL arising from CRLF2-d is five times more frequent among children of Hispanic/Latino ethnicity than others. CRLF2 is part of a signaling receptor activated by ligation with the cytokine TSLP. TSLP has been reported to expand B- ALL cells and to protect them from mTOR inhibitors. Human B-ALL-mouse xenograft models that mimic the in vivo BM environment are the model of choice for identifying therapies that target the mechanisms of chemoresistance that are characteristic of high-risk B-ALL. However, mouse TSLP does not interact with human CRLF2. Thus, existing xenograft models of B-ALL are inadequate for studies of CRLF2-d B-ALL because they do not provide the human TSLP that is required to induce CRLF2-mediated signals. The development of xenograft models of CRLF2 function in B-ALL are essential for identifying therapies that will selectively target CRLF2-d and reduce the health disparity in survival for Hispanic children due to high-risk CRLF2-d B-ALL. The objective of this proposal is to develop an in vivo model of CRLF2 function in B-ALL by expressing human TSLP (hTSLP) in a xenograft model of B-ALL and to use this model to investigate CRLF-2- TSLP interactions as a therapeutic target for high risk CRLF2-d B-ALL. We will achieve this objective through the following aims: Specific Aim 1: Develop a human-mouse xenograft model to identify therapies that will specifically target CRLF2-d B-ALL. We will: 1.1. Engineer immunodeficient mice for lentiviral expression of human hTSLP. 1.2.Optimize the human-mouse xenograft model system for engraftment with CRLF2-d B- ALL cells. Our overarching hypothesis is that TSLP induces CRLF2-mediated signals that are responsible for the disease progression and chemoresistance of CRLF2-d B-ALL that results in poor survival for Hispanic children with B-ALL. To test this hypothesis we will: Specific Aim 2. Determine the impact of CRLF2 ligation on the progression of CRLF2-d B-ALL. Using the hTSLP+/- xenograft model system we will 2.2 Determine the extent of bone marrow disease. 2.3 Evaluate TSLP receptor signaling in B-ALL cells. The xenograft model of CRLF2 function in B-ALL that we will develop in this application will be essential for identifying therapies that will selectively target CRLF2-d and reduce the health disparity in survival for Hispanic children due to high-risk CRLF2-d B-ALL.

描述（由申请人提供）：西班牙裔儿童的死亡率比白人儿童高39％。这种健康差异在生存中的主要原因是缺乏专门针对由失控的CRLF2（CRLF2-D）引起的高风险B-all的疗法。遗传缺陷导致B细胞过表达细胞因子受体成分CRLF2，导致恶性转化和高风险的CRLF2-D B-all，预后不良。 B-由CRLF2-D产生的所有人在西班牙裔/拉丁裔族裔中的频率是其他人的频率的五倍。 CRLF2是通过与细胞因子TSLP连接激活的信号受体的一部分。据报道，TSLP可以扩大所有细胞并保护它们免受MTOR抑制剂的侵害。模仿体内BM环境的人类B-鼠标异种移植模型是识别靶向靶向高危B-all特征的化学耐药机制的疗法的首选模型。但是，小鼠TSLP不与人CRLF2相互作用。因此，现有的B-ALL异种移植模型不足以研究CRLF2-D B-ALL，因为它们不提供诱导CRLF2介导的信号所需的人类TSLP。 B-ALL中CRLF2功能的异种移植模型的发展对于鉴定将有选择地靶向CRLF2-D并降低西班牙裔儿童生存的健康差异至关重要，这是由于高风险CRLF2-D B-ALL所致。该提案的目的是通过在B-All的异种移植模型中表达人类TSLP（HTSLP）来开发B-All中CRLF2功能的体内模型，并使用该模型将CRLF-2-TSLP相互作用作为治疗靶标的高风险CRLF2-D-D-D-D-D-D-D B-all。我们将通过以下目的实现这一目标：特定目标1：开发人鼠异种移植模型，以识别专门针对CRLF2-D B-all的疗法。我们将：1.1。用于人类HTSLP的慢病毒表达的工程师免疫缺陷小鼠。 1.2.将人鼠异种移植模型系统迎合了CRLF2-D B-所有细胞的植入。我们的总体假设是，TSLP诱导CRLF2介导的信号，这些信号导致CRLF2-D B-all的疾病进展和化学抗性，这导致西班牙裔儿童的生存率较差。为了检验该假设，我们将：特定目标2。确定CRLF2连接对CRLF2-D B-all的进展的影响。使用HTSLP +/-异种移植模型系统，我们将2.2确定骨髓疾病的程度。 2.3评估B-所有细胞中的TSLP受体信号传导。我们将在本应用程序中开发的CRLF2功能的异种移植模型对于识别将有选择地靶向CRLF2-D并降低西班牙裔儿童生存的健康差异至关重要。