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RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8;21) AML

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE152335 | GEO | 2021/04/01

REPOSITORIES: GEO

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RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8;21) AML (RNA-Seq)

Project description:Acute myeloid leukemia development occurs in a step-wise fashion whereby an original driver mutation is followed by additional mutations. The first type of mutations tends to be in genes encoding members of the epigenetic/transcription regulatory machinery (i.e. RUNX1, DNMT3, TET2), while the secondary mutations often involve genes encoding members of signalling pathways that cause uncontrolled growth of such cells such as the growth factor receptors c-KIT of FLT3. Patients usually present with both types of mutations, but it is currently unclear how both mutational events shape the epigenome in developing AML cells. To this end we generated an in vitro model of t(8;21) AML by expressing its driver oncoprotein RUNX1-ETO with or without a mutated (N822K) KIT protein. The expression of N822K–c-KIT strongly increases the self-renewal capacity of RUNX1-ETO expressing cells. Global analysis of gene expression changes and alterations in the epigenome show that N822K–c-KIT expression profoundly influences the open chromatin landscape and transcription factor binding. However, our experiments also show that double mutant cells still differ from their patient derived counterparts, highlighting the importance of studying patient cells to obtain a true picture of how gene regulatory networks have been reprogrammed during tumourigenesis.

2021-04-01 | GSE152334 | GEO

RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8;21) AML (ChIP-Seq)

2021-04-01 | GSE152333 | GEO

RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8;21) AML (ATAC-Seq)

2021-04-01 | GSE152332 | GEO

RUNX1-ETO and RUNX1-EVI1 Differentially Reprogram the Chromatin Landscape in t(8;21) and t(3;21) AML.

Project description:Acute myeloid leukemia (AML) is a heterogeneous disease caused by mutations in transcriptional regulator genes, but how different mutant regulators shape the chromatin landscape is unclear. Here, we compared the transcriptional networks of two types of AML with chromosomal translocations of the RUNX1 locus that fuse the RUNX1 DNA-binding domain to different regulators, the t(8;21) expressing RUNX1-ETO and the t(3;21) expressing RUNX1-EVI1. Despite containing the same DNA-binding domain, the two fusion proteins display distinct binding patterns, show differences in gene expression and chromatin landscape, and are dependent on different transcription factors. RUNX1-EVI1 directs a stem cell-like transcriptional network reliant on GATA2, whereas that of RUNX1-ETO-expressing cells is more mature and depends on RUNX1. However, both types of AML are dependent on the continuous expression of the fusion proteins. Our data provide a molecular explanation for the differences in clinical prognosis for these types of AML.

| S-EPMC5457485 | biostudies-literature

RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8;21) AML

Project description:RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8;21) AML

| PRJNA639040 | ENA

RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8;21) AML (ATAC-Seq)

Project description:RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8;21) AML (ATAC-Seq)

| PRJNA639043 | ENA

RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8;21) AML (ChIP-Seq)

Project description:RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8;21) AML (ChIP-Seq)

| PRJNA639044 | ENA

RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8;21) AML (RNA-Seq)

Project description:RUNX1/ETO and mutant KIT both contribute to programming the transcriptional and chromatin landscape in t(8;21) AML (RNA-Seq)

| PRJNA639045 | ENA

The RUNX1-ETO target gene RASSF2 suppresses t(8;21) AML development and regulates Rac GTPase signaling.

Project description:Large-scale chromosomal translocations are frequent oncogenic drivers in acute myeloid leukemia (AML). These translocations often occur in critical transcriptional/epigenetic regulators and contribute to malignant cell growth through alteration of normal gene expression. Despite this knowledge, the specific gene expression alterations that contribute to the development of leukemia remain incompletely understood. Here, through characterization of transcriptional regulation by the RUNX1-ETO fusion protein, we have identified Ras-association domain family member 2 (RASSF2) as a critical gene that is aberrantly transcriptionally repressed in t(8;21)-associated AML. Re-expression of RASSF2 specifically inhibits t(8;21) AML development in multiple models. Through biochemical and functional studies, we demonstrate RASSF2-mediated functions to be dependent on interaction with Hippo kinases, MST1 and MST2, but independent of canonical Hippo pathway signaling. Using proximity-based biotin labeling we define the RASSF2-proximal proteome in leukemia cells and reveal association with Rac GTPase-related proteins, including an interaction with the guanine nucleotide exchange factor, DOCK2. Importantly, RASSF2 knockdown impairs Rac GTPase activation, and RASSF2 expression is broadly correlated with Rac-mediated signal transduction in AML patients. Together, these data reveal a previously unappreciated mechanistic link between RASSF2, Hippo kinases, and Rac activity with potentially broad functional consequences in leukemia.

| S-EPMC7005177 | biostudies-literature

RUNX1-ETO Depletion in t(8;21) AML Leads to C/EBP?- and AP-1-Mediated Alterations in Enhancer-Promoter Interaction.

Project description:Acute myeloid leukemia (AML) is associated with mutations in transcriptional and epigenetic regulator genes impairing myeloid differentiation. The t(8;21)(q22;q22) translocation generates the RUNX1-ETO fusion protein, which interferes with the hematopoietic master regulator RUNX1. We previously showed that the maintenance of t(8;21) AML is dependent on RUNX1-ETO expression. Its depletion causes extensive changes in transcription factor binding, as well as gene expression, and initiates myeloid differentiation. However, how these processes are connected within a gene regulatory network is unclear. To address this question, we performed Promoter-Capture Hi-C assays, with or without RUNX1-ETO depletion and assigned interacting cis-regulatory elements to their respective genes. To construct a RUNX1-ETO-dependent gene regulatory network maintaining AML, we integrated cis-regulatory element interactions with gene expression and transcription factor binding data. This analysis shows that RUNX1-ETO participates in cis-regulatory element interactions. However, differential interactions following RUNX1-ETO depletion are driven by alterations in the binding of RUNX1-ETO-regulated transcription factors.

| S-EPMC6899442 | biostudies-literature

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