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Differential DNA methylation occurs in RUNX1 heterozygous mutations harboring hematopoietic progenitor cells [WES]

ABSTRACT: Background: Familial platelet disorder (FPD) is an autosomal dominant disease caused by a heterozygous germline mutation inRUNX1. FPD patients show not only thrombocytopenia with platelet dysfunction, but also a high level of developing hematological malignancies, strongly suggesting that FPD is in a precancerous state. However, the DNA methylation status of FPD has not yet been elucidated due to no animal models for FPD and the difficulty in obtaining FPD patient-derived samples. Results: We found that differentiation efficiencies into HPCs and megakaryocytes was reduced in the FPD-mimicking cells, which were established by genome editing for human iPS cells as a FPD-model, compared with those of wild-type cells. The FPD-mimicking HPCs were subjected to DNA methylation analysis, and the HPCs showed the distinct DNA methylation patterns compared to wild-type HPCs. Furthermore, we demonstrated a putative causative transcription factor of the differential DNA hypermethylation, which are involved in both promoting the binding site-directed DNA demethylation and regulating megakaryopoiesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245770 | GEO | 2024/02/26

REPOSITORIES: GEO

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Differential DNA methylation occurs in RUNX1 heterozygous mutations harboring hematopoietic progenitor cells [EM]

Project description:Background: Familial platelet disorder (FPD) is an autosomal dominant disease caused by a heterozygous germline mutation inRUNX1. FPD patients show not only thrombocytopenia with platelet dysfunction, but also a high level of developing hematological malignancies, strongly suggesting that FPD is in a precancerous state. However, the DNA methylation status of FPD has not yet been elucidated due to no animal models for FPD and the difficulty in obtaining FPD patient-derived samples. Results: We found that differentiation efficiencies into HPCs and megakaryocytes was reduced in the FPD-mimicking cells, which were established by genome editing for human iPS cells as a FPD-model, compared with those of wild-type cells. The FPD-mimicking HPCs were subjected to DNA methylation analysis, and the HPCs showed the distinct DNA methylation patterns compared to wild-type HPCs. Furthermore, we demonstrated a putative causative transcription factor of the differential DNA hypermethylation, which are involved in both promoting the binding site-directed DNA demethylation and regulating megakaryopoiesis.

2024-02-26 | GSE245765 | GEO

Differential DNA methylation occurs in RUNX1 heterozygous mutations harboring hematopoietic progenitor cells [FLI1_EM]

2024-02-26 | GSE245769 | GEO

Differential DNA methylation occurs in RUNX1 heterozygous mutations harboring hematopoietic progenitor cells [YX-FLI1_EM]

2024-02-26 | GSE249049 | GEO

Targeted correction of RUNX1 mutation in FPD patient-specific induced pluripotent stem cells rescues megakaryopoietic defects

Project description:Familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) is an autosomal dominant disease of the hematopoietic system, which is caused by heterozygous mutations in RUNX1. FPD/AML patients have a bleeding disorder characterized by thrombocytopenia with reduced platelet numbers and functions, and a tendency to develop AML. Currently no suitable animal models exist for FPD/AML as Runx1+/- mice and zebrafish do not develop bleeding disorders or leukemia. Here we derived induced pluripotent stem cells (iPSCs) from two patients in a family with FPD/AML, and found that the FPD iPSCs display defects in megakaryocytic differentiation in vitro. We corrected the RUNX1 mutation in one FPD iPSC line through gene targeting, which led to normalization of megakaryopoiesis of the iPSCs in culture. Our results demonstrate successful in vitro modeling of FPD with patient-specific iPSCs and confirm that RUNX1 mutations are responsible for megakaryopoietic defects in FPD patients.

2014-07-01 | GSE54295 | GEO

Targeted correction of RUNX1 mutation in FPD patient-specific induced pluripotent stem cells rescues megakaryopoietic defects

2014-07-01 | E-GEOD-54295 | biostudies-arrayexpress

ABCC4 impacts megakaryopoiesis and protects megakaryocytes against 6-mercaptopurine induced cytotoxicity [RNA-seq Mouse]

Project description:The role of ABCC4, an ATP-binding cassette transporter, in the process of platelet formation, megakaryopoiesis, is unknown. Here, we show that ABCC4 is highly expressed in megakaryocytes (MKs). Mining of public genomic data (ATAC-seq and genome wide chromatin interactions, Hi-C) revealed that key megakaryopoiesis transcription factors (TFs) interacted with ABCC4 regulatory elements and likely accounted for high ABCC4 expression in MKs. Importantly these genomic interactions for ABCC4 ranked higher than for genes with known roles in megakaryopoiesis suggesting a role for ABCC4 in megakaryopoiesis. We then demonstrate that ABCC4 is required for optimal platelet formation as in vitro differentiation of fetal liver derived MKs from Abcc4-/- mice exhibited impaired proplatelet formation and polyploidization, features required for optimal megakaryopoiesis. Likewise, a human megakaryoblastic cell line, MEG-01 showed that acute ABCC4 inhibition markedly suppressed key processes in megakaryopoiesis and that these effects were related to reduced cAMP export and enhanced dissociation of a negative regulator of megakaryopoiesis, protein kinase A (PKA) from ABCC4. PKA activity concomitantly increased after ABCC4 inhibition which was coupled with significantly reduced GATA-1 expression, a TF needed for optimal megakaryopoiesis. Further, ABCC4 protected MKs from 6-mercaptopurine (6-MP) as Abcc4-/- mice show a profound reduction in MKs after 6-MP treatment. In total, our studies show that ABCC4 not only protects the MKs but is also required for maximal platelet production from MKs, suggesting modulation of ABCC4 function might be a potential therapeutic strategy to regulate platelet production.

2024-01-05 | GSE234628 | GEO

ABCC4 impacts megakaryopoiesis and protects megakaryocytes against 6-mercaptopurine induced cytotoxicity [RNA-seq Human]

2024-01-05 | GSE234560 | GEO

Transcription profiling of human CD34+ cells from familial platelet disorder

Project description:Characterize the genes deregulated in CD34 positive cells from peripheral blood of FPD/AML patients harbouring two different RUNX1 mutations. RUNX1 (also called AML1), a DNA-binding subunit of the CBF transcription factor family, is a master regulatory gene in hematopoiesis and acts as a tumour suppressor. Heterozygous germ line alterations in RUNX1 lead to a familial platelet disorder with a propensity to develop acute myeloid leukemia (FPD/AML). Although RUNX1 abnormalities per se are not sufficient to induce full-blown leukemia in FPD, this pathology represents a valuable model to understand how RUNX1 germ line mutations predispose to acquisition of additional genetic changes leading to leukemia transformation. To investigate how RUNX1 may predispose to leukemia, we performed a comparative study between two pedigrees harbouring different RUNX1 mutations, one associated with only thrombocytopenia (R139stop) and the other leading to thrombocytopenia and leukemic predisposition (R174Q).

2010-09-11 | E-TABM-792 | biostudies-arrayexpress

Efficacy of novel agents against cellular models of familial platelet disorder with myeloid malignancy (FPD-MM). [ChIP-Seq]

Project description:Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.

2024-02-01 | GSE252739 | GEO

Efficacy of novel agents against cellular models of familial platelet disorder with myeloid malignancy (FPD-MM). [scRNA-Seq]

2024-02-01 | GSE252745 | GEO

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