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细胞从增殖期过渡到分化期所必需的。在Ikaros丧失后，大量增殖的前b细胞急剧积累，并在这一发育阶段受阻。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）的正常发育对口物，在这一阶段阻断可能致瘤性。IKAROS在人类B-ALL中经常失活，并且在大多数BCR-ABL B-ALL中观察到其缺失，这定义了一种特别具有侵袭性和难以治疗的白血病。在此，我们建议建立Ikaros在b细胞前分化过程中支持的细胞和分子途径，并描述其中的调控机制。Ikaros是染色质重塑复合体的一个组成部分，通过调节其靶位点附近的染色质发挥作用。因此，本研究的部分目的是了解正常、白血病前期和白血病前期b细胞阶段的表观遗传调控。在第一个特定目标中，我们将描述Ikaros丢失对控制过渡到前b细胞阶段的细胞和分子途径的影响。我们将研究BCR-ABL是否以及如何进一步调节ikaros依赖性b细胞前通路的活性，并在B-ALL中建立两个因子之间的潜在协同作用或合作关系。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。Ikaros对基因靶位点染色质可及性的影响，以及对该过程中其他关键转录和染色质调控因子的招募的影响将被评估。我们还将评估基于ikaros的调控过程是否也由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最新的全基因组基因表达、染色质和信号传导方法相结合，以描述这些因素在正常B细胞分化和白血病发展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/定制诊断和治疗高风险B-ALL。

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. .