Function of SATB1 as a critical regulator in acute myeloid leukemia

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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.