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

摘要： 西班牙裔儿童更有可能患上急性淋巴细胞白血病(ALL)，当这种情况发生时，他们 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细胞前体的一种亚型 ALL(B-ALL)在西班牙裔儿童中发生的频率是其他儿童的五倍，并具有较高的 复发率。这种类型的白血病被称为CRLF2 B-ALL，其特征是两种基因改变：a) 细胞因子受体CRLF2的过度表达和b)Ikaros的一个等位基因的缺失或失活 (IKZF1)肿瘤抑制因子，与复发密切相关。我们的总体假设是 选择性地针对CRLF2 B-ALL(CRLF2和CRLF2)中解除调控的通路的联合治疗 Ikaros)将产生优越的治疗效果和降低死亡率，以缩小健康差距 西班牙裔儿童与ALL的生存。当CRLF2受体被其下游的配体TSLP激活时 促进白血病细胞存活、增殖和增殖的途径(JAK/STAT和PI3/AKT/mTOR) 化疗耐药是通过通常由Ikaros肿瘤抑制因子控制的过程来诱导的。 我们团队的初步数据显示，用CK2特异性抑制剂CX-4945治疗可以恢复伊卡洛斯 缺失一个Ikaros等位基因的西班牙裔高危B-ALL患者的肿瘤抑制功能 有很强的体内治疗效果。CRLF2B-ALL的临床前研究通常使用患者来源的异种移植 (PDX)模型，其中CRLF2B-ALL患者的原代白血病细胞被注射到免疫系统中 有缺陷的小鼠。我们的初步数据显示，小鼠TSLP不能激活人类CRLF2，使 目前的PDX模型不适用于CRLF2 B-ALL的研究。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鼠)并产生PDX的免疫缺陷小鼠 给这些小鼠注射来自西班牙裔儿童患者的CRLF2B-ALL细胞(+T PDX)。对+T PDX的分析 显示CRLF2激活和基因表达与原始患者样本比标准样本更相似 PDX。我们的初步数据为新疗法提供了理论基础，这种疗法针对的是由 CRLF2(JAK-STAT5和PI3K/AKT/mTOR)和使用我们新的- 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：建立 靶向CRLF2下游通路的体内治疗效果及其在西班牙裔B-ALL中的作用 儿科病人。目的2：评价综合疗法在体内的疗效及作用机制 在西班牙裔儿童CRLF2B-ALL中，Ikaros肿瘤抑制活性和mTOR途径被抑制。这个 建议的研究使用精确医学方法(针对特定的通路和/或功能缺陷) 健康差距背景下开发CRLF2B-ALL的新疗法并减少 儿童癌症健康差距。

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.