Ikaros regulation: study on hemo-lymphopoiesis

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细胞从增殖阶段过渡到分化阶段所必需的。在Ikaros丧失后，大量增殖的前B细胞急剧积累，并在此发育阶段出现障碍。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)的正常发育阶段，在这个阶段是潜在的致癌障碍。Ikaros在人类B-ALL中经常失活，在大多数BCR-ABL B-ALL中观察到它的丢失，这定义了一种特别侵袭性和难以治疗的白血病。在这里，我们建议建立在前B细胞分化过程中由Ikaros支持的细胞和分子通路，并描述相关的调控机制。Ikaros是染色质重塑复合体的组成部分，通过调节其靶点附近的染色质发挥功能。因此，这项研究的一部分旨在了解正常、白血病前期和白血病前B细胞阶段的表观遗传学调节。在第一个具体目标中，我们将描述Ikaros缺失对控制前B细胞阶段过渡的细胞和分子通路的影响。我们将研究BCR-ABL是否以及如何进一步调节依赖于Ikaros的前B细胞通路的活性，并在B-ALL中建立两个因素之间的潜在协同或合作。在第二个目标中，我们将建立由Ikaros直接调控的基因网络和采用的表观遗传机制。将评估Ikaros对其基因靶点的染色质可及性以及这一过程中其他关键转录和染色质调节因子的招募的影响。我们还将评估基于Ikaros的监管过程是否也由BCR-ABL控制。基于BCR-ABL的Ikaros功能丧失和功能获得的新遗传模型将与前沿的全基因组基因表达、染色质和信号方法相结合，以描绘这些因素在正常B细胞分化和白血病发生过程中影响的表观遗传、转录和信号网络。利用Ikaros基因靶点或其转录和表观遗传调控机制可能有助于设计新的智能/量身定制的高危B-ALL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功能在这个阶段失效时，B细胞表型不成熟的癌症是如何发展的。了解Ikaros如何在正常和异常的B细胞发育中发挥作用，可以帮助设计新的智能和量身定制的诊断和治疗方法来治疗淋巴癌。

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.