Similar Datasets
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
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
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 | GSE194170 | GEO
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 | GSE186146 | GEO
Project description:PU.1-dependent enhancer inhibition separates Tet2 deficient clonal hematopoiesis from malignant transformation
| PRJNA789544 | ENA
Project description:PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (oxBS-Seq)
| PRJNA799349 | ENA
Project description:PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (ATAC-Seq)
| PRJNA789545 | ENA
Project description:PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (RNA-Seq)
| PRJNA772735 | ENA
Project description:Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of proinflammatory cytokines, including interleukin-1β (IL-1β). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1β, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177 824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] ≥2%: odds ratio [OR], 1.69; 95% CI, 1.09-2.61; P = .0189; UKB, CHIP with VAF ≥10%: OR, 1.25; 95% CI, 1.05-1.50; P = .0133). Moreover, individuals with CHIP and a VAF ≥10% had an increased risk of incident gout (UKB: hazard ratio [HR], 1.28; 95% CI, 1.06-1.55; P = .0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1β secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1β in response to MSU crystals in vitro, which was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1β levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in patients with gout.
| S-EPMC9461470 | biostudies-literature
Project description:Clonal hematopoiesis of indeterminate potential (CHIP), also referred to as aging-related clonal hematopoiesis, is defined as an asymptomatic clonal expansion of mutant mature hematopoietic cells in ≥4% of blood leukocytes. CHIP associates with advanced age and increased risk for hematological malignancy, cardiovascular disease, and all-cause mortality. Loss-of-function somatic mutations in TET2 are frequent drivers of CHIP. However, the contribution of aging-associated cooperating cell-extrinsic drivers, like inflammation, remains underexplored. Using bone marrow (BM) transplantation and newly developed genetic mosaicism (HSC-SCL-Cre-ERT; Tet2+/flox; R26+/tm6[CAG-ZsGreen1]Hze) mouse models of Tet2+/-driven CHIP, we observed an association between increased Tet2+/- clonal expansion and higher BM levels of the inflammatory cytokine interleukin-1 (IL-1) upon aging. Administration of IL-1 to mice carrying CHIP led to an IL-1 receptor 1 (IL-1R1)-dependent expansion of Tet2+/- hematopoietic stem and progenitor cells (HSPCs) and mature blood cells. This expansion was caused by increased Tet2+/- HSPC cell cycle progression, increased multilineage differentiation, and higher repopulation capacity compared with their wild-type counterparts. In agreement, IL-1α-treated Tet2+/- hematopoietic stem cells showed increased DNA replication and repair transcriptomic signatures and reduced susceptibility to IL-1α-mediated downregulation of self-renewal genes. More important, genetic deletion of IL-1R1 in Tet2+/- HPSCs or pharmacologic inhibition of IL-1 signaling impaired Tet2+/- clonal expansion, establishing the IL-1 pathway as a relevant and therapeutically targetable driver of Tet2+/- CHIP progression during aging.
| S-EPMC10651783 | biostudies-literature