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%，是导致癌症的主要原因 儿童和年轻人的癌症死亡率。白血病是一种发育中的祖细胞的癌症， 儿童白血病最常见的亚型是前体B细胞急性淋巴母细胞 白血病(前B-ALL)亚型。虽然B型前白血病的治疗在最近几年有了很大的改善，但有 仍然是预后差、治疗选择有限的白血病亚型，复发仍然是一种 这是个大问题。这些亚型中的一些可以由特定的遗传损伤来表征。突变或 编码转录因子Ikaros的IKZF1基因的缺失定义了这样一个高危亚群。伊卡洛斯 对淋巴系发育至关重要，在前B淋巴细胞白血病中被认为是重要的肿瘤抑制因子。 尤其是在BCR-ABL1+(Ph+)Pre-B ALL中，其中Ikaros功能丧失突变在大于 80%的病例，在新定义的高危bcr-abl1阴性“类Ph”亚类中。尽管有这么多油井- Ikaros作为肿瘤抑制因子在前B-ALL中的作用已有文献记载，但对Ikaros如何 抑制白血病的功能。此外，这种强关联的分子机制 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BALL前的Ikaros功能丧失的治疗方法。我们 建议研究伊卡洛斯突变的Ph+白血病的独特特征，以帮助合理设计 有针对性的治疗，我们将重点放在Ikaros功能的关键方面。首先，正如伊卡洛斯突变所显示的那样 导致祖细胞限制基因(包括‘茎’基因)的异常表达，我们将测试 在Ikaros突变的Pre-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，我们将研究伊卡洛斯的机制 作为染色质结构的调节器，并最终研究表观遗传抑制物是否可以用于 在IKZF1突变的Pre-B ALL中模拟Ikaros肿瘤抑制功能(目标2)。此外，我们将调查 Ph+Pre-B法检测bcr-abl1癌基因与IKZF1-突变的特异性协同作用 ALL具有由IKZF1标记的特定染色质可及性签名-突变是 BCR-ABL1下游通路(目标3)。这项研究的结果可能为新的功能靶点提供 诊断和治疗IKZF1突变的Pre-B ALL，并将为表观遗传学提供关键的见解 合理使用表观遗传调节剂治疗白血病的调节失调。