Targeting CRLF2 and Ikaros Alterations to Reduce Health Disparities in Childhood Leukemia

以 CRLF2 和 Ikaros 改变为目标，减少儿童白血病的健康差异

• 批准号: 9753178
• 负责人: Sinisa Dovat
• 金额: $ 34.97万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753178
• 关键词: Acute Lymphocytic Leukemia; Affect; Alleles; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Cell Cycle; Cell Proliferation; Cell Survival; Cessation of life; Child; Childhood; Childhood Leukemia; Combined Modality Therapy; Cytokine Receptors; Data; Death Rate; Defect; Disease Progression; Engineering; Epigenetic Process; FRAP1 gene; Gene Expression; Genes; Genetic; Hispanics; Human; Ikaros protein; Immune; Impairment; JAK2 gene; Knowledge; Latino; Leukemic Cell; Ligands; Malignant Childhood Neoplasm; Measures; Molecular; Mus; Mutation; Not Hispanic or Latino; Oncogenic; PI3 gene; PI3K/AKT; Pathway interactions; Patients; Pharmacotherapy; Phosphotransferases; Pre-Clinical Model; Process; Proto-Oncogene Proteins c-akt; Relapse; Repression; Role; Sampling; Serum; Sirolimus; Stat5 protein; TSLP gene; Testing; Therapeutic; Therapeutic Effect; Time; Treatment Efficacy; Tumor Suppressor Proteins; Xenograft Model; Xenograft procedure; base; cancer health disparity; disease mechanisms study; health disparity; high risk; in vivo; inhibitor/antagonist; leukemia; mTOR Inhibitor; mTOR Signaling Pathway; mTOR inhibition; mortality; new therapeutic target; novel; novel therapeutics; overexpression; pediatric patients; precision medicine; preclinical study; receptor; restoration

SUMMARY  Hispanic children are more likely to develop acute lymphocytic leukemia (ALL), and when this occurs they are 39% more likely to die than non-Hispanic Whites. This disparity is due, in part, to a subtype of B-cell precursor ALL (B-ALL) that occurs five times more frequently among Hispanic children than others and has a high relapse rate. This type of leukemia, called CRLF2 B-ALL, is characterized by two genetic alterations: a) overexpression of the cytokine receptor, CRLF2, and b) deletion or inactivation of one allele of the Ikaros (IKZF1) tumor suppressor which is strongly associated with relapse. Our overall hypothesis is that combination therapy that selectively targets the pathways that are deregulated in CRLF2 B-ALL (CRLF2 and Ikaros) will produce a superior therapeutic effect and decrease mortality to reduce the health disparity in survival for Hispanic children with ALL. When the CRLF2 receptor is activated by its ligand, TSLP, downstream pathways (JAK/STAT and PI3/AKT/mTOR) that promote leukemia cell survival, proliferation, and chemoresistance are induced through processes normally kept in check by the Ikaros tumor suppressor. Preliminary data from our team show that treatment with the CK2-specific inhibitor, CX-4945, restores Ikaros tumor suppressor function in high-risk B-ALL from Hispanic patients with deletion of one Ikaros allele, exerting a strong in vivo therapeutic effect. Preclinical studies of CRLF2 B-ALL typically use patient-derived xenograft (PDX) models, where primary leukemia cells from patients with CRLF2 B-ALL are injected into immune deficient mice. Our preliminary data show that mouse TSLP does not activate human CRLF2, making the current PDX models suboptimal for studies of CRLF2 B-ALL. To overcome this obstacle our team engineered immune deficient mice that provide normal human serum levels of human TSLP (+T mice) and generated PDX by injecting these mice with CRLF2 B-ALL cells from Hispanic pediatric patients (+T PDX). Analysis of +T PDX shows CRLF2 activation and gene expression that is more similar to original patient sample than standard PDX. Our preliminary data provide a rationale for novel therapy that targets pathways that are induced by CRLF2 (JAK-STAT5 and PI3K/AKT/mTOR) and by loss of Ikaros tumor suppressor activity using our newly- developed preclinical model for Hispanic CRLF2 B-ALL. To test our hypothesis we will: Aim 1: Establish the in vivo therapeutic efficacy of targeting CRLF2 downstream pathways and their role in CRLF2 B-ALL in Hispanic pediatric patients. Aim 2: Evaluate the in vivo efficacy and mechanisms of combination therapy that restores Ikaros tumor suppressor activity and inhibits the mTOR pathway in Hispanic pediatric CRLF2 B-ALL. The proposed studies use precision medicine approaches (targeting specific pathways and/or functional defects) in context of the health disparity background to develop a novel treatment for CRLF2 B-ALL and reduce childhood cancer health disparities.

概括 西班牙裔儿童更有可能患上急性淋巴细胞性白血病（全部），当这种情况发生时 死亡的可能性比非西班牙裔白人高39％。这种差异部分归因于B细胞前体的亚型 西班牙裔儿童中所有（B-all）的发生频率高五倍，并且具有很高的 复发率。这种类型的白血病（称为CRLF2 B-all）的特征是两个遗传改变：a） 细胞因子受体，CRLF2和B）ikaros的一个等位基因的删除或灭活的过表达 （IKZF1）与继电器密切相关的肿瘤抑制剂。我们的总体假设是 合并疗法有选择地靶向在CRLF2 B-ALL中受管制的途径（CRLF2和 ikaros）将产生卓越的热效应并降低死亡率，以降低健康差异 与所有人的西班牙裔孩子的生存。当CRLF2受体被其配体TSLP激活时 促进白血病生存，增殖和 化学抗性是通过通常由Ikaros肿瘤抑制剂检查的过程来诱导的。 我们团队的初步数据表明，用CK2特异性抑制剂CX-4945恢复Ikaros的治疗 来自西班牙裔患者的高风险B-all肿瘤抑制器功能，其中一个ikaros等位基因的缺失 强大的体内治疗作用。 CRLF2 B的临床前研究通常使用患者衍生的异种移植 （PDX）模型，其中来自CRLF2 B-ALL患者的原发性白血病细胞被注入免疫 不足的小鼠。我们的初步数据表明，小鼠TSLP不会激活人Crlf2，使得 当前的PDX模型用于CRLF2 B-ALL研究的次优。为了克服这一障碍，我们的团队设计了 免疫缺陷小鼠提供正常的人血清水平的人类TSLP（+T小鼠）并产生的PDX 通过向这些小鼠注射来自西班牙裔小儿患者（+T PDX）的CRLF2 B-ALL细胞。 +T PDX的分析 显示CRLF2激活和基因表达与原始患者样本更相似 PDX。我们的初步数据为新颖疗法提供了一种基本原理，该疗法针对由 CRLF2（JAK-STAT5和PI3K/AKT/MTOR）以及使用我们的新抑制剂活性损失 开发了西班牙裔CRLF2 B-All的临床前模型。为了检验我们的假设，我们将：目标1：确定 靶向CRLF2下游途径及其在CRLF2 B-ALL中的作用的体内疗法有效性 小儿患者。目标2：评估恢复的组合疗法的体内效率和机制 Ikaros肿瘤抑制活性，并抑制西班牙裔小儿CRLF2 B-ALL中的MTOR途径。这 拟议的研究使用精确的医学方法（针对特定途径和/或功能缺陷） 健康差异背景的背景是为CRLF2 b-all开发新的治疗方法并减少 儿童癌症健康分布。