Understanding Ikaros molecular functions for targeted therapies of pre-B ALL

了解 Ikaros 分子功能用于前 B ALL 靶向治疗

基本信息

批准号：
9750657
负责人：
Seth E Frietze
金额：
$ 34.95万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-25 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9750657
关键词：
ABL1 gene ATAC-seq Acute Lymphocytic Leukemia Address B-Cell Acute Lymphoblastic Leukemia Bioinformatics Biological Biological Assay Biological Models Blood Cells Cancer Etiology Cell Surface Proteins ChIP-seq Child Child Mortality Chromatin Chromatin Remodeling Factor Chromatin Structure Collaborations Complement Data Detection Development Diagnosis Epigenetic Process FDA approved Gene Expression Gene Expression Regulation Genes Genetic Goals Growth Hematopoietic Hematopoietic Neoplasms Human Individual Knowledge Lesion Leukemic Cell Link Logic Lymphoid Malignant Childhood Neoplasm Malignant Neoplasms Mediator of activation protein Modeling Molecular Morbidity - disease rate Mus Mutate Mutation Newly Diagnosed Oncogenes Oncogenic Outcome Pathogenesis Pathway interactions Patients Pre-B Acute Lymphoblastic Leukemia Process Property Recurrence Regulation Relapse Reporting Research Role Signal Transduction Stat5 protein Subgroup Testing Tumor Suppressor Genes Tumor Suppressor Proteins Tumor-Suppressor Gene Inactivation abl Oncogene actionable mutation cancer diagnosis cell growth cell transformation design functional genomics genetic approach high risk histone modification human model improved inhibitor/antagonist insight leukemia leukemia treatment loss of function loss of function mutation mortality mouse model outcome forecast pediatric patients personalized medicine progenitor programs public health relevance side effect stemness targeted treatment therapeutic target thymocyte transcription factor transcriptome young adult

项目摘要

ABSTRACT Blood cancer constitutes nearly 10% of all newly diagnosed cancer cases in the US and is the leading cause of cancer mortality for children and young adults. Leukemia is a cancer of developing progenitor blood cells, and the most common subtype of leukemia in pediatric patients is the precursor B-cell acute lymphoblastic leukemia (pre-B ALL) subtype. While treatment for pre-B ALL has improved greatly in recent years, there are still subtypes of leukemia that have poor prognosis and limited treatment options, and relapse remains a significant problem. Some of these subtypes can be characterized by specific genetic lesions. Mutations or deletions in the IKZF1 gene encoding the transcription factor Ikaros define one such high-risk subgroup. Ikaros is critical for lymphoid development and is recognized as an important tumor suppressor in pre-B ALL, in particular in BCR-ABL1+ (Ph+) pre-B ALL, where Ikaros loss-of-function mutations are found in greater than 80% of cases, and in the newly defined high-risk BCR-ABL1-negative “Ph-like” subclass. In spite of the well- documented role of Ikaros as a tumor suppressor in pre-B ALL, there is limited understanding of how Ikaros functions to suppress leukemia. Furthermore, the molecular mechanisms underlying the strong association between the BCR-ABL1 oncogene and loss of Ikaros tumor suppressor function is poorly understood. Importantly, there are currently no therapies available that target Ikaros loss-of-function in pre-B ALL. We propose to study the unique features of Ikaros-mutated Ph+ leukemia in order to aid in rational design of targeted therapies, and we will focus on key aspects of Ikaros function. First, as Ikaros mutations are shown to result in aberrant expression of progenitor-restricted genes (including `stemness' genes), we will test the functional role of selected cell-surface proteins aberrantly expressed in Ikaros-mutated pre-B ALL, and evaluate their growth- or survival-promoting properties (Aim 1). Second, we will study the mechanism of Ikaros as a regulator of chromatin structure and ultimately investigate if epigenetic inhibitors can be employed to mimic Ikaros tumor suppressor function in IKZF1-mutated pre-B ALL (Aim 2). Furthermore, we will investigate the specific collaboration between the BCR-ABL1 oncogene and IKZF1-mutations by evaluating if Ph+ pre-B ALL has a specific chromatin accessibility signature enabeled by IKZF1-mutations that is required for the downstream BCR-ABL1 pathways (Aim 3). The results of this study may provide new functional targets for diagnosis and treatment of IKZF1-mutated pre-B ALL, and will provide critical insight into epigenetic dysregulation in leukemia for the rational use of epigenetic modulators for treatment.

抽象的血癌占美国所有新诊断癌症病例的近 10%，是导致癌症的主要原因儿童和年轻人的癌症死亡率白血病是一种祖细胞发育中的癌症，并且儿科患者最常见的白血病亚型是前体 B 细胞急性淋巴细胞白血病白血病（B 期前 ALL）亚型虽然近年来 B 期前 ALL 的治疗已取得很大进展，但仍存在一些问题。白血病的亚型仍然具有较差的预后和有限的治疗选择，并且复发仍然是一个问题其中一些亚型可能具有特定的基因突变或特征。编码转录因子 Ikaros 的 IKZF1 基因的缺失定义了这样一个高风险亚组。对于淋巴系统的发育至关重要，并被认为是前 B ALL 中的重要肿瘤抑制因子，在特别是在 BCR-ABL1+ (Ph+) pre-B ALL 中，其中发现 Ikaros 功能丧失突变大于 80% 的病例，以及新定义的高风险 BCR-ABL1 阴性“Ph 样”亚类。已有文献记载 Ikaros 在 B 期 ALL 中作为肿瘤抑制剂的作用，但对 Ikaros 如何发挥作用的了解还很有限此外，强关联背后的分子机制。 BCR-ABL1 癌基因与 Ikaros 肿瘤抑制功能丧失之间的关系尚不清楚。重要的是，目前还没有针对 B ALL 前期 Ikaros 功能丧失的治疗方法。提议研究 Ikaros 突变 Ph+ 白血病的独特特征，以帮助合理设计靶向治疗，我们将重点关注 Ikaros 功能的关键方面，因为 Ikaros 突变已被证明。导致祖细胞限制基因（包括“干性”基因）的异常表达，我们将测试在 Ikaros 突变的前 B ALL 中异常表达的选定细胞表面蛋白的功能作用，以及评估其促进生长或促进生存的特性（目标 1）。其次，我们将研究 Ikaros 的机制。作为染色质结构的调节剂，并最终研究是否可以使用表观遗传抑制剂模拟 Ikaros 肿瘤抑制功能在 IKZF1 突变的 pre-B ALL 中的作用（目标 2）。通过评估 Ph+ pre-B 是否可以确定 BCR-ABL1 癌基因和 IKZF1 突变之间的特定协作 ALL 具有由 IKZF1 突变启用的特定染色质可及性特征，这是下游 BCR-ABL1 通路（目标 3）本研究的结果可能为 BCR-ABL1 通路提供新的功能靶点。 IKZF1 突变前 B ALL 的诊断和治疗，并将提供对表观遗传学的重要见解白血病失调，合理使用表观遗传调节剂进行治疗。