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PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (RNA-Seq)

ABSTRACT: PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (RNA-Seq)

PROVIDER: PRJNA772735 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16483767_1.fastq.gz	Fastqsanger.gz
	SRR16483767_2.fastq.gz	Fastqsanger.gz
	SRR16483768_1.fastq.gz	Fastqsanger.gz
	SRR16483768_2.fastq.gz	Fastqsanger.gz
	SRR16483769_1.fastq.gz	Fastqsanger.gz

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PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (oxBS-Seq)

Project description:PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (oxBS-Seq)

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PU.1-dependent enhancer inhibition separates Tet2 deficient clonal hematopoiesis from malignant transformation

Project description:PU.1-dependent enhancer inhibition separates Tet2 deficient clonal hematopoiesis from malignant transformation

| PRJNA789544 | ENA

PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (ATAC-Seq)

Project description:PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (ATAC-Seq)

| PRJNA789545 | ENA

PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (ATAC-Seq)

Project description:Hematopoietic stem cells sustain life-long blood production. While they are the known cellular origin of aging-associated myeloid malignancies, such as acute myeloid leukemia (AML), mechanisms driving their malignant transformation have remained elusive. Epigenetic dysregulation following acquired loss-of-function mutations of DNA methyl-cytosine dioxygenase Ten-Eleven Translocation-2 (TET2) occurs frequently in the elderly leading to cytosine hypermethylation in and around DNA binding sites of master transcription factors, including PU.1. Here we show that Tet2 deficient hematopoietic stem and progenitor cells (HSPC) undergo malignant transformation upon compromised PU.1 gene regulation. Leukemic stem and progenitor cells show hypermethylation at PU.1 binding sites and fail to activate PU.1-depenent myeloid enhancers, and are hallmarked by a defined signature of impaired genes shared with human AML. Our study demonstrates that Tet2 and PU.1 cooperate in suppressing leukemogenesis in HSPC and establishes a methylation sensitive PU.1-dependent gene network as a unifying feature in acute myeloid leukemia.

2022-07-31 | GSE191052 | GEO

PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (oxBS-Seq)

2022-07-31 | GSE194170 | GEO

PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (RNA-Seq)

2022-07-31 | GSE186146 | GEO

PU.1-Dependent Enhancer Inhibition Separates Tet2-Deficient Hematopoiesis from Malignant Transformation.

Project description:Cytosine hypermethylation in and around DNA-binding sites of master transcription factors, including PU.1, occurs in aging hematopoietic stem cells following acquired loss-of-function mutations of DNA methyl-cytosine dioxygenase ten-eleven translocation-2 (TET2), albeit functional relevance has been unclear. We show that Tet2-deficient mouse hematopoietic stem and progenitor cells undergo malignant transformation upon compromised gene regulation through heterozygous deletion of an upstream regulatory region (UREΔ/WT) of the PU.1 gene. Although compatible with multilineage blood formation at young age, Tet2-deficient PU.1 UREΔ/WT mice develop highly penetrant, transplantable acute myeloid leukemia (AML) during aging. Leukemic stem and progenitor cells show hypermethylation at putative PU.1-binding sites, fail to activate myeloid enhancers, and are hallmarked by a signature of genes with impaired expression shared with human AML. Our study demonstrates that Tet2 and PU.1 jointly suppress leukemogenesis and uncovers a methylation-sensitive PU.1-dependent gene network as a unifying molecular vulnerability associated with AML.SignificanceWe identify moderately impaired PU.1 mRNA expression as a biological modality predisposing Tet2-deficient hematopoietic stem and progenitor cells to malignant transformation. Our study furthermore uncovers a methylation-sensitive PU.1 gene network as a common feature of myeloid leukemia potentially allowing for the identification of patients at risk for malignant transformation. See related commentary by Schleicher and Pietras, p. 378. This article is highlighted in the In This Issue feature, p. 369.

| S-EPMC9894728 | biostudies-literature

PU.1-dependent enhancer inhibition separates Tet2 deficient clonal hematopoiesis from malignant transformation

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

2022-07-31 | GSE191053 | GEO

Transcription profiling of hematopoietic stem cells in the preleukemic phase from wiltype mice and mice deficient in transcription factor PU.1 to identify transcriptional changes preceding malignant transformation

Project description:Knockdown of the transcription factor PU.1 (Spi1) leads to acute myeloid leukemia (AML) in mice. We examined the transcriptome of PU.1 knockdown hematopoietic stem cells (HSC) in the preleukemic phase by linear amplification and genome-wide array analysis to identify transcriptional changes preceding malignant transformation. Hierarchical cluster analysis and principal component analysis clearly distinguished PU.1 knockdown from wildtype HSC. Jun family transcription factors c-Jun and JunB were among the top downregulated targets. Retroviral restoration of c-Jun expression in bone marrow cells of preleukemic mice partially rescued the PU.1-initiated myelomonocytic differentiation block. Lentiviral restoration of JunB at the leukemic stage led to reduced clonogenic growth, loss of leukemic self-renewal capacity, and prevented leukemia in transplanted NOD-SCID mice. Examination of 305 AML patients confirmed the correlation between PU.1 and JunB downregulation and suggests its relevance in human disease. These results delineate a transcriptional pattern that precedes the leukemic transformation in PU.1 knockdown HSC and demonstrate that decreased levels of c-Jun and JunB contribute to the development of PU.1-induced AML by blocking differentiation (c-Jun) and increasing self-renewal (JunB). Therefore, examination of disturbed gene expression in HSC can identify genes whose dysregulation is essential for leukemic stem cell function and are targets for therapeutic interventions. Experiment Overall Design: Total RNA of HSC of PU.1 knockdown or wildtype animals (3 pools of 3 animals each) was amplified by two rounds of RT and T7 promoter-based in-vitro transcription and the resultant biotinylated cRNA was then hybridized to Affymetrix Mouse Genome 430 2.0 arrays.

2007-11-22 | E-GEOD-5654 | biostudies-arrayexpress

Sequentially inducible mouse models reveal that Npm1 mutation causes malignant transformation of Dnmt3a-mutant clonal hematopoiesis.

Project description:Clonal hematopoiesis (CH) is a common aging-associated condition with increased risk of hematologic malignancy. Knowledge of the mechanisms driving evolution from CH to overt malignancy has been hampered by a lack of in vivo models that orthogonally activate mutant alleles. Here, we develop independently regulatable mutations in DNA methyltransferase 3A (Dnmt3a) and nucleophosmin 1 (Npm1), observed in human CH and AML, respectively. We find Dnmt3a mutation expands hematopoietic stem and multipotent progenitor cells (HSC/MPPs), modeling CH. Induction of mutant Npm1 after development of Dnmt3a-mutant CH causes progression to myeloproliferative disorder (MPD), and more aggressive MPD is observed with longer latency between mutations. MPDs uniformly progress to acute myeloid leukemia (AML) following transplant, accompanied by a decrease in HSC/MPPs and an increase in myeloid-restricted progenitors, the latter of which propagate AML in tertiary recipient mice. At a molecular level, progression of CH to MPD is accompanied by selection for mutations activating Ras/Raf/MAPK signaling. Progression to AML is characterized by additional oncogenic signaling mutations (Ptpn11, Pik3r1, Flt3) and/or mutations in epigenetic regulators (Hdac1, Idh1, Arid1a). Together, our study demonstrates that Npm1 mutation drives evolution of Dnmt3a-mutant CH to AML and rate of disease progression is accelerated with longer latency of CH.

| S-EPMC6609470 | biostudies-literature

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