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.

总结 西班牙裔儿童更容易患急性淋巴细胞白血病（ALL），当这种情况发生时， 死亡可能性比非西班牙裔白人高出39%。这种差异部分是由于B细胞前体的亚型 ALL（B-ALL）在西班牙裔儿童中发生的频率是其他儿童的五倍， 复发率这种类型的白血病称为CRLF 2 B-ALL，其特征在于两种遗传改变： 细胞因子受体CRLF 2的过表达，和B）Ikaros的一个等位基因的缺失或失活 （IKZF 1）肿瘤抑制因子，与复发密切相关。我们的总体假设是 选择性靶向CRLF 2 B-ALL中失调的通路（CRLF 2和 Ikaros）将产生上级治疗效果，降低死亡率，以缩小 西班牙裔儿童ALL的生存率。当CRLF 2受体被其配体TSLP激活时，下游 促进白血病细胞存活、增殖的信号通路（JAK/STAT和PI 3/AKT/mTOR）， 化学抗性是通过通常由Ikaros肿瘤抑制因子控制的过程诱导的。 我们团队的初步数据显示，用CK 2特异性抑制剂CX-4945治疗， 在一个Ikaros等位基因缺失的西班牙裔高危B-ALL患者中， 体内治疗效果强。CRLF 2 B-ALL的临床前研究通常使用患者来源的异种移植物 (PDX)模型，其中来自CRLF 2 B-ALL患者的原代白血病细胞被注射到免疫系统中， 缺陷小鼠我们的初步数据显示，小鼠TSLP不激活人CRLF 2，使得 目前的PDX模型对于CRLF 2 B-ALL研究而言是次优的。为了克服这个障碍，我们的团队设计了 提供正常人血清水平的人TSLP（+T小鼠）并产生PDX的免疫缺陷小鼠 通过给这些小鼠注射来自西班牙裔儿科患者的CRLF 2 B-ALL细胞（+T PDX）。+T PDX分析 显示CRLF 2活化和基因表达与原始患者样品比标准样品更相似 PDX我们的初步数据提供了一个理论基础，新的治疗目标的途径，诱导 CRLF 2（JAK-STAT 5和PI 3 K/AKT/mTOR）和Ikaros肿瘤抑制活性的丧失，使用我们的新方法， 开发了西班牙裔CRLF 2 B-ALL的临床前模型。为了验证我们的假设，我们将：目标1：建立在 靶向CRLF 2下游通路的体内治疗效果及其在西班牙裔CRLF 2 B-ALL中的作用 儿科患者。目的2：评价联合治疗的体内疗效和机制， Ikaros肿瘤抑制活性和抑制西班牙裔儿童CRLF 2 B-ALL的mTOR通路的 拟议的研究使用精确医学方法（针对特定途径和/或功能缺陷）， 在健康差异背景下，开发CRLF 2 B-ALL的新型治疗方法， 儿童癌症健康差距。