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Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance

ABSTRACT: Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance

PROVIDER: PRJNA848763 | ENA |

REPOSITORIES: ENA

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

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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.

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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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