Function of SATB1 as a critical regulator in acute myeloid leukemia

在造血系统中，只有造血干细胞(HSCs)能够分化为所有功能的血细胞，并在没有分化的情况下产生新的HSCs。平衡HSC的自我更新和分化对于长期维持一个有功能的HSC池至关重要，而静止期和激活期平衡的改变被认为会导致恶性转化。癌症干细胞(CSCs)与非恶性组织特异性干细胞具有共同的关键特征。特定转录因子的相互作用指示正常的组织特异性干细胞，如造血干细胞，以高度特异的方式发挥作用。人们承认，在正常的造血过程中，某些关键的转录因子必须以精确的空间和时间方式受到严密的调控，以确保组织的完整性。然而，表观遗传机制对基因表达的调控，特别是在干细胞中的调控，目前还没有完全阐明。染色质重塑蛋白在上位基因表达调控中发挥作用，可能提供缺失的功能环节。染色质重塑因子特别是富含AT的序列结合蛋白1(SATB1)通过直接控制转录主调控子的基因表达参与了红系和髓系的分化。依赖Satb1的基因调控已经与表观遗传改变联系在一起，如组蛋白修饰和DNA甲基化，并在决定HSC命运的过程中起着关键作用。此外，初步数据显示，SATB1在正常的HSC和祖细胞中高表达，而在AML患者来源的白血病启动细胞(LIC)中表达减弱。这项拟议项目的目的是确定SATB1是否可能作为急性髓系白血病的表观遗传抑制因子发挥作用。有待检验的假设是，SATB1通过改变DNA甲基化模式以及随后干细胞相关基因调控网络的变化来发挥其抗白血病作用，从而保护造血干细胞和祖细胞免受白血病转化。为了解决这个问题，我们想要在活体内结合I类白血病突变来分析SATB1在LSCs中的功能，并利用转基因小鼠模型和下一代测序方法来确定SATB1缺陷AML的表观遗传学特征和功能相关的靶基因。更好地理解染色质重塑蛋白如何平衡干细胞中的染色质以随后与转录因子结合，最终可能使我们能够将这些蛋白质用于白血病的靶向治疗方法。由于表观遗传改变不会改变DNA序列本身，并且在药物上是可逆的，它们被认为是有希望的治疗靶点。

Within the hematopoietic system, only hematopoietic stem cells (HSCs) are able to both differentiate into all functional blood cells and to give rise to new HSCs without differentiation. Balancing the self-renewal and differentiation of HSCs is crucial for long-term maintenance of a functional HSC pool, and alterations in the balance of quiescence and activation are known to lead to malignant transformation. Cancer stem cells (CSCs) share key features with non-malignant tissue-specific stem cells. The interplay of specific transcription factors instructs normal tissue-specific stem cells, such as HSCs, to function in a highly specific manner. It is acknowledged that certain key transcription factors must be tightly regulated in a precise spatial and temporal manner during normal hematopoiesis to ensure tissue integrity. However, gene expression regulation by epigenetic mechanisms, especially in stem cells, has not been fully elucidated yet. Chromatin remodeling proteins play a role in superordinate gene expression regulation and may provide the missing functional link. The chromatin-remodeling factor Special AT-rich sequence-binding protein 1 (SATB1) has been implicated in erythroid and myeloid differentiation by directly controlling gene expression of transcriptional master regulators. Satb1-dependent gene regulation has already been linked to epigenetic alterations, such as histone modifications and DNA methylation, and is critically involved in HSC fate determination. Moreover, preliminary data showed that SATB1 is highly expressed in normal HSC and progenitors while its expression is impaired in AML patient-derived leukemia initiating cells (LIC). The aim of the proposed project is to determine whether SATB1 might function as an epigenetic suppressor of acute myeloid leukemia. The hypothesis to be tested is that SATB1 exerts its anti-leukemic effect through altered DNA methylation patterns and subsequent changes in a stem cell-related gene regulatory network, thereby protecting hematopoietic stem and progenitor cells from leukemic transformation. To address this question, we want to analyze the function of SATB1 in LSCs in cooperation with class I leukemogenic mutations in vivo and define the epigenetic signature and functionally relevant target genes in SATB1-deficient AML using transgenic mouse models and next generation sequencing methods. Improved understanding of how chromatin-remodeling proteins poise chromatin in stem cells for subsequent binding of transcription factors might ultimately enable us to exploit these proteins for targeted therapy approaches in leukemia. Since epigenetic alterations do not alter the DNA sequence itself and are pharmacologically reversible, they have been considered promising targets for therapy.