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

• 批准号: 10203874
• 负责人: Seth E Frietze
• 金额: $ 36.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/10203874
• 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; Prognosis; 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; cancer diagnosis; cell growth; cell transformation; design; driver mutation; 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; pediatric patients; personalized medicine; progenitor; programs; public health relevance; side effect; stemness; targeted treatment; therapeutic target; thymocyte; transcription factor; transcriptome; young adult

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 血液癌占美国所有新诊断的癌症病例的几乎10％，是 儿童和年轻人的癌症死亡率。白血病是祖细胞发育中的癌症， 小儿患者白血病最常见的亚型是前体B细胞急性淋巴细胞 白血病（pre-b all）亚型。尽管近年来，pre-b的治疗都大大改善，但 仍然是预后较差和有限治疗选择的白血病的亚型，并且继电器仍然是一种 重大问题。这些亚型中的一些可以以特定的遗传病变为特征。突变或 编码转录因子ikaros的IKZF1基因中的删除定义了这样的高风险亚组。 对于淋巴发育至关重要，被认为是pre-b all中的重要肿瘤抑制剂 在BCR-ABL1+（pH+）pre-b中，特别是在ikaros功能丧失突变中发现大于大于 80％的病例，以及新定义的高风险BCR-ABL1阴性“类似pH”子类。尽管有 伊卡罗斯（Ikaros 抑制白血病的功能。此外，强缔合的基本机制 在BCR-ABL1癌基因和Ikaros肿瘤抑制功能的丧失之间，人们对此很少了解。 重要的是，目前尚无针对ikaros在pre-b全部丧失功能的疗法。我们 研究ikaros突变的pH+白血病的独特特征，以帮助合理设计 有针对性的疗法，我们将专注于Ikaros功能的关键方面。首先，正如ikaros突变所显示的那样 导致祖细胞限制基因的异常表达（包括“茎”基因），我们将测试 在Ikaros-Mutated Pre-B中异常表达的选定细胞表面蛋白的功能作用， 评估其生长或生存促进特性（AIM 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聘请表观遗传抑制剂 模仿IKAROS肿瘤抑制剂在IKZF1突变的pre-b全部（AIM 2）中。此外，我们将调查 通过评估pH+ pre-b 所有人都有由IKZF1-刺激启用的特定染色质可访问性签名 下游BCR-ABL1途径（AIM 3）。这项研究的结果可能会为 ikzf1突变的pre-b全部诊断和治疗，将提供对表观遗传的关键见解 白血病的失调，用于将表观遗传调节剂合理使用治疗。