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

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

PROVIDER: PRJNA848774 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19635877_1.fastq.gz	Fastqsanger.gz
	SRR19635877_2.fastq.gz	Fastqsanger.gz
	SRR19635878_1.fastq.gz	Fastqsanger.gz
	SRR19635878_2.fastq.gz	Fastqsanger.gz
	SRR19635879_1.fastq.gz	Fastqsanger.gz

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Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance

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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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Epigenetic mechanisms controlling human leukemia stem cells and therapy resistance

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

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Interrogating bromodomain inhibitor resistance in KMT2A-rearranged leukemia through combinatorial CRISPR screens

Project description:Bromo- and extra-terminal domain inhibitors (BETi) have exhibited therapeutic activities in many cancers, including KMT2A-rearranged (KMT2A-r) leukemia, in preclinical studies. However, the mechanisms controlling BETi response and resistance are poorly understood. We conducted genome-wide loss-of-function CRISPR screens using BETi-treated KMT2A-r cell lines. SPOP gene deficiency caused significant BETi resistance, which was further validated in cell line and xenograft models. In SPOP-knockout KMT2A-r leukemia cells, TRIM24 was identified as a SPOP substrate that mediates resistance to BETi. Additionally, proteomics analysis and a kinase-vulnerability CRISPR screen indicated that resistant cells are sensitive to GSK3 inhibition. Genetically perturbating TRIM24 or pharmaceutical inhibition of its downstream target GSK3 in SPOP-knockout cells reversed the BETi-resistance phenotype. A combination therapy regimen inhibiting both BET and GSK3 impeded leukemia progression in patient-derived xenografts in vivo. Our results revealed not only novel molecular mechanisms underlying BETi resistance but also a promising strategy for treating KMT2A-r leukemia.

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Mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance

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