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Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance [RNA-seq]

ABSTRACT: Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance [RNA-seq]

PROVIDER: PRJNA848772 | ENA |

REPOSITORIES: ENA

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Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance

Project description:Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance

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Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance [ATAC-seq]

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Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance [RNA-seq]

Project description:Many human cancers, including acute myeloid leukemia (AML), arise from mutations of stem and progenitor cells. Immunophenotypic profiling has shown that leukemia develops hierarchically, with mutations in leukemia stem cells associated with disease propagation and relapse1,2. Although leukemia initiating cells can be enriched using cell surface markers, their frequency tends to be variable and low, obscuring mechanisms and hindering effective therapies3,4. To define AML stem cells in human patients, we performed functional genomic profiling of diverse leukemias using label tracing techniques designed to preserve hematopoietic stem cell (HSC) function in vivo. We found that propagation of human AML is mediated by a rare but distinct quiescent label-retaining cell (LRC) population that evades detection by currently known immunophenotypic markers. We show that human AML LRC quiescence is reversible, sparing genetic clonal competition that maintains its epigenetic inheritance. LRC quiescence is defined by distinct promoter-centered chromatin and gene expression dynamics, and controlled by a novel AP-1/ETS transcription factor network, which is associated with disease persistence and chemotherapy resistance in diverse patients. These results enable prospective isolation and functional genetic manipulation of immunophenotypically-varied leukemia stem cells in human patient specimens, as well as establish the key functions of epigenetic plasticity in leukemia development and therapy resistance. We anticipate that these findings will lead to the elucidation of essential properties of leukemia stem cell quiescence and the design of therapeutic strategies for their clinical identification and control.

2024-06-28 | GSE205993 | GEO

Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance [ATAC-seq]

2024-06-28 | GSE205989 | GEO

Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-06-28 | GSE205994 | GEO

Mechanisms Controlling Human Microglia Gene Expression

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Emerging Epigenetic and Posttranslational Mechanisms Controlling Resistance to Glucocorticoids in Acute Lymphoblastic Leukemia.

Project description:Glucocorticoids are extensively used for the treatment of acute lymphoblastic leukemia as they pressure cancer cells to undergo apoptosis. Nevertheless, glucocorticoid partners, modifications, and mechanisms of action are hitherto poorly characterized. This hampers our understanding of therapy resistance, frequently occurring in leukemia despite the current therapeutic combinations using glucocorticoids in acute lymphoblastic leukemia. In this review, we initially cover the traditional view of glucocorticoid resistance and ways of targeting this resistance. We discuss recent progress in our understanding of chromatin and posttranslational properties of the glucocorticoid receptor that might be proven beneficial in our efforts to understand and target therapy resistance. We discuss emerging roles of pathways and proteins such as the lymphocyte-specific kinase that antagonizes glucocorticoid receptor activation and nuclear translocation. In addition, we provide an overview of ongoing therapeutic approaches that sensitize cells to glucocorticoids including small molecule inhibitors and proteolysis-targeting chimeras.

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Novel epigenetic based differentiation therapy for Acute Myeloid Leukemia

Project description:We have identified and characterized two lysine (K) deacetylase inhibitors (DACi), CM-444 and CM-1758. These inhibitors demonstrate the ability to promote myeloid differentiation in all acute myeloid leukemia (AML) subtypes at low, non-cytotoxic doses, setting them apart from other commercially available histone deacetylase inhibitors (HDACi). Upon analysis of the acetylome following treatment with CM-444 and CM-1758, we observed modulation of non-histone proteins involved in the enhancer–promoter chromatin regulatory complex, including bromodomain proteins (BRDs). This acetylation is crucial for enhancing the expression of key transcription factors directly involved in the differentiation therapy induced by CM-444 and CM-1758 in AML. In summary, these compounds present promising potential as effective differentiation-based therapeutic agents across AML subtypes, offering a novel mechanism for the treatment of AML

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Novel epigenetic based differentiation therapy for Acute Myeloid Leukemia

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Project description:Novel epigenetic based differentiation therapy for Acute Myeloid Leukemia

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