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: 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
• 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

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.

摘要 在美国，血癌占所有新诊断癌症病例的近10%，并且是癌症的主要原因。 儿童和年轻人的癌症死亡率。白血病是一种发展中的祖血细胞的癌症， 儿童患者中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（前B ALL）亚型。虽然近年来前B ALL的治疗有了很大的改善，但 白血病的亚型仍然预后不良，治疗选择有限，复发仍然是一个问题。 重大问题。这些亚型中的一些可以通过特定的遗传病变来表征。突变或 编码转录因子Ikaros的IKZF 1基因的缺失定义了一个这样的高风险亚组。Ikaros 对淋巴发育至关重要，被认为是前B ALL的重要肿瘤抑制因子， 特别是在BCR-ABL 1+（Ph+）前B ALL中，其中在大于100例患者中发现Ikaros功能丧失突变。 80%的病例，以及新定义的高危BCR-ABL 1阴性“Ph样”亚类。尽管如此- Ikaros在前B ALL中作为肿瘤抑制剂的作用已有记录，但对Ikaros如何作用的了解有限。 抑制白血病的功能。此外，强关联的分子机制 BCR-ABL 1癌基因与Ikaros肿瘤抑制功能缺失之间的关系尚不清楚。 重要的是，目前还没有针对前B ALL中Ikaros功能丧失的治疗方法。我们 建议研究Ikaros突变Ph+白血病的独特特征，以帮助合理设计 靶向治疗，我们将专注于Ikaros功能的关键方面。首先，由于Ikaros突变被证明是 导致祖先限制基因（包括“干性”基因）的异常表达，我们将测试 Ikaros突变前B ALL中异常表达的选定细胞表面蛋白的功能作用，以及 评估其促进生长或存活的特性（目标1）。第二，研究Ikaros的作用机制 作为染色质结构的调节剂，并最终研究表观遗传抑制剂是否可以用于 在IKZF 1突变的前B ALL中模拟Ikaros肿瘤抑制功能（Aim 2）。此外，我们将调查 BCR-ABL 1癌基因和IKZF 1突变之间的特异性协作，通过评估Ph+前B ALL具有由IKZF 1突变实现的特定染色质可及性特征，这是ALL发生所需的。 下游BCR-ABL 1通路（Aim 3）。本研究结果可能为神经胶质瘤的治疗提供新的功能靶点。 IKZF 1突变的前B ALL的诊断和治疗，并将为表观遗传学 在白血病中的调节异常，以合理使用表观遗传调节剂进行治疗。