Ikaros regulation: study on hemo-lymphopoiesis

Ikaros 调节：造血淋巴细胞的研究

• 批准号: 8188058
• 负责人: KATIA GEORGOPOULOS
• 金额: $ 36.73万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8188058
• 关键词: Apoptotic; Atypical lymphocyte; B Cell Proliferation; B cell differentiation; B-Cell Acute Lymphoblastic Leukemia; B-Cell Development; B-Lymphocytes; Biological Models; Cell Differentiation process; Cells; Chromatin; Chromatin Remodeling Factor; Chronic Lymphocytic Leukemia; DNA Binding; Defect; Development; Diagnostic; Disease; Epigenetic Process; Gene Expression; Gene Targeting; General Transcription Factors; Genes; Genetic; Genetic Models; Genetic Transcription; Growth; Human; In Vitro; Life; Lymphocyte Function; Lymphoid; Lymphopoiesis; Malignant Neoplasms; Molecular; Mus; Mutation; Nature; Nuclear Protein; Nucleosomes; Outcome Study; Pathway interactions; Phase; Phenotype; Process; Proliferating; Property; Regulation; Rest; Signal Pathway; Signal Transduction; Site; Staging; System; T-Lymphocyte; Transcription Coactivator; Transcriptional Regulation; Work; base; bcr-abl Fusion Proteins; design; empowered; feeding; gain of function; genome-wide; high risk; in vivo; insight; leukemia; loss of function; migration; mutant; operation; promoter; synergism; tumorigenic

DESCRIPTION (provided by applicant): Our recent studies indicate that the DNA binding factor Ikaros is required for pre-B cell transition from a proliferating to a differentiating phase. Upon Ikaros loss there is a dramatic accumulation of large proliferating pre-B cells and a block at this developmental stage. Proliferating pre-B cell are considered the normal developmental counterpart of B cell acute lymphoblastic leukemia (B-ALL), and a block at this stage potentially tumorigenic. IKAROS is frequently inactivated in human B-ALL, and its loss is observed in the majority of BCR-ABL B-ALL, defining a particularly aggressive and hard-to-treat leukemia. Here, we propose to establish the cellular and molecular pathways supported by Ikaros during pre-B cell differentiation and delineate the regulatory mechanisms involved. Ikaros is an integral component of a chromatin remodeling complex and functions by modulating chromatin in the vicinity of its target sites. Therefore part of this study aims at understanding the epigenetic regulation of the normal, pre- leukemic, and leukemic pre-B cell stages. In the first specific aim, we will delineate the effects of Ikaros loss on the cellular and molecular pathways that control transition through the pre-B cell stage. We will examine whether and how activity of Ikaros-dependent pre-B cell pathways are further modulated by BCR-ABL and establish a potential synergism or co-operation between the two factors in B-ALL. In the second aim, we will establish the gene networks that are directly regulated by Ikaros and the epigenetic mechanisms employed. Ikaros effects on chromatin accessibility at its gene target sites and on recruitment of other key transcriptional and chromatin regulators of this process will be evaluated. We will also evaluate whether the Ikaros-based regulatory process is also controlled by BCR-ABL. New genetic models based on Ikaros loss-of-function and gain of function for BCR-ABL will be combined with cutting-edge genome-wide gene expression, chromatin and signaling approaches to delineate the epigenetic, transcription and signaling networks effected by these factors during normal B cell differentiation and leukemia development. Exploitation of the Ikaros gene targets or their transcriptional and epigenetic mechanisms of regulation may empower the design of new intelligent/tailored diagnostics and therapies for high-risk B-ALL. . PUBLIC HEALTH RELEVANCE: Here we investigate the mechanisms by which the nuclear protein Ikaros controls normal development of B cells. We study how cancers with an immature B cell phenotype develop when Ikaros function fail sat this stage. Understanding how Ikaros works in normal and abnormal B cell development can empower the design of new intelligent and tailored diagnostics and therapies to cure lymphoid cancers.

描述（由申请人提供）：我们最近的研究表明，DNA结合因子Ikaros是前B细胞从增殖期向分化期转变所必需的。在Ikaros损失后，存在大的增殖前B细胞的急剧积累和在该发育阶段的阻滞。增殖的前B细胞被认为是B细胞急性淋巴细胞白血病（B-ALL）的正常发育对应物，并且在该阶段的阻滞可能具有致瘤性。IKAROS在人类B-ALL中经常失活，并且在大多数BCR-ABL B-ALL中观察到其丢失，这定义了一种特别具有侵袭性和难以治疗的白血病。在这里，我们建议建立细胞和分子途径支持Ikaros在前B细胞分化和描绘的监管机制。Ikaros是染色质重塑复合物的组成部分，通过调节其靶位点附近的染色质发挥作用。因此，本研究的一部分旨在了解正常、白血病前和白血病前B细胞阶段的表观遗传调控。在第一个具体目标中，我们将描述Ikaros损失对控制前B细胞阶段过渡的细胞和分子途径的影响。我们将研究Ikaros依赖的前B细胞通路的活性是否以及如何进一步由BCR-ABL调节，并在B-ALL中建立两种因子之间的潜在协同作用或合作。在第二个目标中，我们将建立由Ikaros直接调控的基因网络和所采用的表观遗传机制。将评估Ikaros对其基因靶位点的染色质可及性以及该过程中其他关键转录和染色质调节因子的募集的影响。我们还将评估Ikaros调控过程是否也受BCR-ABL控制。基于Ikaros功能丧失和BCR-ABL功能获得的新遗传模型将与尖端的全基因组基因表达、染色质和信号转导方法相结合，以描绘在正常B细胞分化和白血病发展过程中受这些因素影响的表观遗传、转录和信号转导网络。对Ikaros基因靶点或其转录和表观遗传调控机制的利用可能会为高风险B-ALL设计新的智能/定制诊断和治疗方法。. 公共卫生相关性：在这里，我们研究核蛋白Ikaros控制B细胞正常发育的机制。我们研究了当Ikaros功能在这个阶段失败时，具有不成熟B细胞表型的癌症是如何发展的。了解Ikaros如何在正常和异常B细胞发育中发挥作用，可以设计新的智能和定制的诊断和治疗方法来治愈淋巴癌。