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The mitochondrial metabolic enzyme Hexokinase 2 regulates stem cell function and differentiation by increasing chromatin openness and the accessibility of stem cell genes [ChIP-Seq]

ABSTRACT: Mitochondrial metabolites regulate the function and differentiation of leukemic and normal stem cells by affecting epigenetic marks. However, it is less understood how mitochondrial enzymes localize to the nucleus to control stem cell function. We discovered that the mitochondrial metabolic enzyme Hexokinase 2 (HK2) localizes to the nucleus in leukemic and normal hematopoietic stem cells. Overexpression of nuclear HK2 increased leukemic stem cell (LSC) properties and decreased differentiation while selective knockdown of nuclear HK2 promoted differentiation and decreased stem cell function. The nuclear localization of HK2 was phosphorylation dependent and required active import and export. Nuclear HK2 regulated LSC and differentiation independent of its enzymatic and metabolic activity. HK2 interacted with nuclear proteins that regulate chromatin openness and increased chromatin accessibilities at sites associated with the LSC+ signature and DNA damage repair. Consistent with these effects, nuclear HK2 increased repair of DNA damage and contributed to the mechanism by which LSCs resist DNA damaging agents. Thus, we describe a non-canonical mechanism by which mitochondrial enzymes regulate gene expression and stem cell function independent of their metabolic function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE176072 | GEO | 2022/03/15

REPOSITORIES: GEO

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The mitochondrial metabolic enzyme Hexokinase 2 regulates stem cell function and differentiation by increasing chromatin openness and the accessibility of stem cell genes [ATAC-Seq]

Project description:Mitochondrial metabolites regulate the function and differentiation of leukemic and normal stem cells by affecting epigenetic marks. However, it is less understood how mitochondrial enzymes localize to the nucleus to control stem cell function. We discovered that the mitochondrial metabolic enzyme Hexokinase 2 (HK2) localizes to the nucleus in leukemic and normal hematopoietic stem cells. Overexpression of nuclear HK2 increased leukemic stem cell (LSC) properties and decreased differentiation while selective knockdown of nuclear HK2 promoted differentiation and decreased stem cell function. The nuclear localization of HK2 was phosphorylation dependent and required active import and export. Nuclear HK2 regulated LSC and differentiation independent of its enzymatic and metabolic activity. HK2 interacted with nuclear proteins that regulate chromatin openness and increased chromatin accessibilities at sites associated with the LSC+ signature and DNA damage repair. Consistent with these effects, nuclear HK2 increased repair of DNA damage and contributed to the mechanism by which LSCs resist DNA damaging agents. Thus, we describe a non-canonical mechanism by which mitochondrial enzymes regulate gene expression and stem cell function independent of their metabolic function.

2022-03-15 | GSE176071 | GEO

The mitochondrial metabolic enzyme Hexokinase 2 regulates stem cell function and differentiation by increasing chromatin openness and the accessibility of stem cell genes [RNA-Seq]

2022-03-15 | GSE176103 | GEO

In vivo CRISPR screening unveils RNA binding protein dependencies for leukemic stem cells and identifies ELAVL1 as a potential therapeutic target [RNA-seq]

Project description:RNA binding protein (RBP)-directed post-transcriptional control of stem cell fate represents an underexplored mechanism driving hematopoietic stemness and transformation. We show that a unique set of RBPs are specifically enriched in leukemic stem cells (LSCs) of human primary acute myeloid leukemia (AML) but repressed in normal hematopoietic stem cells. Using an in vivo CRISPR-Cas9-mediated screening approach, we identify 33 key RBPs specifically essential for LSC-mediated MLL-AF9/NrasG12D AML. Knock-down/genetic ablation of the hit RBP Elavl1 in genetically distinct leukemias significantly reduced LSC numbers, and hampered leukemic engraftment. In human AML we show impairment of LSC-driven in vivo leukemic reconstitution and selective depletion of AML progenitors upon ELAVL1 targeting, highlighting the potential clinical importance of our findings. Profiling of the leukemic ELAVL1-mRNA interactome revealed hematopoietic differentiation, RNA splicing and mitochondrial metabolism as major pathways impacted by ELAVL1. Altogether, this work demonstrates that Elavl1 and other RBPs are critical regulators of LSC-survival and self-renewal.

2023-01-18 | GSE127743 | GEO

In vivo CRISPR screening unveils RNA binding protein dependencies for leukemic stem cells and identifies ELAVL1 as a potential therapeutic target [eCLIPseq]

2023-01-18 | GSE127944 | GEO

A two-step in vivo CRISPR screen unveils pervasive RNA binding protein dependencies for leukemic stem cells and identifies ELAVL1 as a therapeutic target

Project description:Acute myeloid leukemia (AML) progression and relapse is fueled by self-renewing leukemic stem cells (LSCs) whose molecular determinants have been difficult to discern from normal hematopoietic stem cells (HSCs) or to uncover in screening approaches focused on general AML cell properties. We have identified a unique set of RNA binding proteins (RBPs) that are enriched in human AML LSCs but repressed in HSCs. Using an in vivo two step CRISPR-Cas9-mediated screening approach to specifically score for cancer stem cell functionality, we found 32 RBPs essential for LSC propagation and self- renewal in MLL-AF9 translocated AML. Using knockdown or small molecule approaches we show that targeting key hit RBP ELAVL1 impaired LSC-driven in vivo leukemic reconstitution and selectively depleted primitive AML cells vs. normal hematopoietic stem and progenitors. Importantly, knockdown of Elavl1 spared HSCs while significantly reducing LSC numbers across genetically diverse leukemias. Integrative RNA-seq and eCLIP-seq profiling revealed hematopoietic differentiation, RNA splicing and mitochondrial metabolism as key features defining the leukemic ELAVL1-mRNA interactome with the mitochondrial import protein TOMM34 being a direct ELAVL1-stabilized target whose inhibition impairs AML propagation.

2023-03-13 | GSE224548 | GEO

Disrupting mitochondrial copper distribution inhibits leukemic stem cell self-renewal

Project description:Leukemic stem cells (LSC) rely on oxidative metabolism and are differentially sensitive to targeting mitochondrial pathways, which spares normal hematopoietic cells. A subset of mitochondrial proteins are folded in the intermembrane space via the mitochondrial intermembrane assembly (MIA) pathway. We found increased mRNA expression of MIA pathway substrates in acute myeloid leukemia (AML) stem cells. Therefore, we evaluated the effects of inhibiting this pathway in AML. Genetic and chemical inhibition of ALR reduces AML growth and viability, disrupts LSC self-renewal and induces their differentiation. ALR inhibition preferentially decreases its substrate COX17, a mitochondrial copper chaperone and knockdown of COX17 phenocopies ALR loss. Inhibiting ALR and COX17 increases mitochondrial copper levels which in turn inhibit S-Adenosylhomocysteine Hydrolase (SAHH) and lower levels of S-adenosylmethionine (SAM), DNA methylation, and chromatin accessibility to lower LSC viability. These results provide insight into mechanisms through which mitochondrial copper controls epigenetic status and viability of LSCs.

2020-04-14 | GSE146252 | GEO

Gene expression profiles of AML derived stem cells: similarity to hematopoietic stem cells

Project description:Tumors contain a fraction of cancer stem cells that maintain the propagation of the disease. The CD34‏CD38_ cells, isolated from acute myeloid leukemia (AML), were shown to be enriched leukemic stem cells (LSC). We isolated the CD34‏CD38_ cell fraction from AML and compared their gene expression profiles to the CD34‏CD38‏ cell fraction, using microarrays. We found 409 genes that were at least twofold over- or underexpressed between the two cell populations. These include underexpression of DNA repair, signal transduction and cell cycle genes, consistent with the relative quiescence of stem cells, and chromosomal aberrations and mutations of leukemic cells. Comparison of the LSC expression data to that of normal hematopoietic stem cells (HSC) revealed that 34% of the modulated genes are shared by both LSC and HSC, supporting the suggestion that the LSC originated within the HSC progenitors. We focused on the Notch pathway since Jagged-2, a Notch ligand was found to be overexpressed in the LSC samples. We show that DAPT, an inhibitor of gamma-secretase, a protease that is involved in Jagged and Notch signaling, inhibits LSC growth in colony formation assays. Identification of additional genes that regulate LSC self-renewal may provide new targets for therapy. Microarrays were used to compare the gene expression patterns between AML CD34+CD38- cells and AML CD34+CD38+

2011-12-01 | E-GEOD-34044 | biostudies-arrayexpress

DYRK2 stabilization has dual effects on apoptosis and self-renewal of leukemia stem cells that can be targeted in chronic myeloid leukemia

Project description:Gene expression analysis of leukemic stem cells (LSC) from WT and KLF4-deficient BCR-ABL p210-induced chronic myeloid leukemia (CML) mice Loss of Klf4 impairs self-renewal and survival of LSC in CML. Analysis provides insight into function of KLF4 in leukemia.

2018-12-31 | GSE100909 | GEO

miR-126 Governs Human Leukemia Stem Cell Quiescence and Therapeutic Resistance

Project description:In acute myeloid leukemia (AML), leukemia stem cells (LSC) play a central role in disease progression and recurrence due to their intrinsic capacity for self-renewal and chemotherapy resistance. Whereas epigenetic mechanisms balance normal blood stem cell self-renewal and fate decisions, mutation and dysregulation of epigenetic regulators are considered fundamental to leukemia initiation and progression. Alterations in miRNA function represent a non-canonical epigenetic mechanism influencing malignant hematopoiesis, however the function of miRNA in human LSC remains undetermined. Here we show that miRNA profiling of fractionated AML populations defines an LSC-specific signature that is highly prognostic for patient survival. Gain- and loss-of-function analyses demonstrated that miR-126 restrained cell cycle progression, prevented differentiation, and increased self-renewal of human LSC. By targeting the G0 to G1 gatekeeper CDK3, miR-126 preserved LSC quiescence and promoted chemotherapy resistance. Thus, in AML, miRNAs influence patient outcome through post-transcriptional regulation of stemness programs in LSC.

2016-03-31 | PXD001994 | Pride

Bortezomib suppresses self-renewal and leukemogenesis of leukemia stem cell by NF-ĸB-dependent inhibition of cyclin dependent kinase 6 in MLL-rearranged myeloid leukemia

Project description:Acute myeloid leukemia (AML) with chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukemia (MLL) is an aggressive subtype with low overall survival. MLL rearrangements rapidly transform hematological stem and progenitor cell (HSPC) to leukemia stem cell (LSC). Bortezomib (Velcade) is used widely in hematological malignancies. However, it is still unknown whether bortezomib possesses anti-self-renewal and anti-leukemogenesis of LSC in AML with MLL rearrangements. Here, we found that bortezomib inhibited cell proliferation, induced apoptosis, and decreased colony formation in leukemic cell lines, primary AML blasts, and MLL-AF9-transformed murine leukemic blasts. Besides, bortezomib reduced the frequency and function of LSC, inhibited the progression, and prolonged

2022-08-10 | GSE157702 | GEO

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