Hematopoietic stem cells acquire survival advantage by loss of RUNX1 methylation identified in familial leukemia
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PROVIDER: PRJNA622962 | ENA |
REPOSITORIES: ENA
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Project description:RUNX1 is among the most frequently mutated genes in human leukemia, and the loss or dominant-negative suppression of RUNX1 function is found in myelodysplastic syndrome and acute myeloid leukemia (AML). However, how post-translational modifications (PTMs) of RUNX1 affect its in vivo function and whether PTM dysregulation of RUNX1 can cause leukemia are largely unknown. We performed targeted deep sequencing on a family with 3 occurrences of AML and identified a novel RUNX1 mutation R237K. The mutated R237 residue is a methylation site by PRMT1 and loss of methylation has been reported to impair transcriptional activity of RUNX1 in vitro. To explore biological significance of RUNX1 methylation in vivo, we utilized RUNX1 R233K/R237K double mutant mice, in which 2 arginine-to-lysine mutations precluded RUNX1 methylation. Genetic ablation of RUNX1 methylation led to loss of quiescence and expansion of hematopoietic stem cells (HSCs), and changed the genomic and epigenomic signature of phenotypic HSCs to a poised progenitor state. Further, loss of RUNX1 R233/R237 methylation suppressed endoplasmic reticulum stress-induced unfolded protein response genes including Atf4, Ddit3, and Gadd34, radiation-induced p53 downstream genes, Bbc3, Pmaip1, and Cdkn1a, and subsequent apoptosis in HSCs. Mechanistically, ATF4 was identified as a direct transcriptional target of RUNX1. Collectively, defects in RUNX1 methylation in HSCs confer resistance to apoptosis and survival advantage under stress conditions, a hallmark of a pre-leukemic clone which may predispose affected individuals to leukemia. Our study will lead to a better understanding of how dysregulation of PTMs can contribute to leukemogenesis.
2020-07-06 | GSE148051 | GEO
Project description:Hematopoietic stem cells acquire survival advantage by loss of RUNX1 methylation identified in familial leukemia [ATAC-seq]
| PRJNA623453 | ENA
Project description:RUNX1 is among the most frequently mutated genes in human leukemia, and the loss or dominant-negative suppression of RUNX1 function is found in myelodysplastic syndrome and acute myeloid leukemia (AML). However, how post-translational modifications (PTMs) of RUNX1 affect its in vivo function and whether PTM dysregulation of RUNX1 can cause leukemia are largely unknown. We performed targeted deep sequencing on a family with 3 occurrences of AML and identified a novel RUNX1 mutation R237K. The mutated R237 residue is a methylation site by PRMT1 and loss of methylation has been reported to impair transcriptional activity of RUNX1 in vitro. To explore biological significance of RUNX1 methylation in vivo, we utilized RUNX1 R233K/R237K double mutant mice, in which 2 arginine-to-lysine mutations precluded RUNX1 methylation. Genetic ablation of RUNX1 methylation led to loss of quiescence and expansion of hematopoietic stem cells (HSCs), and changed the genomic and epigenomic signature of phenotypic HSCs to a poised progenitor state. Further, loss of RUNX1 R233/R237 methylation suppressed endoplasmic reticulum stress-induced unfolded protein response genes including Atf4, Ddit3, and Gadd34, radiation-induced p53 downstream genes, Bbc3, Pmaip1, and Cdkn1a, and subsequent apoptosis in HSCs. Mechanistically, ATF4 was identified as a direct transcriptional target of RUNX1. Collectively, defects in RUNX1 methylation in HSCs confer resistance to apoptosis and survival advantage under stress conditions, a hallmark of a pre-leukemic clone which may predispose affected individuals to leukemia. Our study will lead to a better understanding of how dysregulation of PTMs can contribute to leukemogenesis.
2020-07-06 | GSE148201 | GEO
Project description:Mutations in the RUNX1 gene (RUNX1mut) have been established in myelodysplasia (MDS), de novo and secondary acute myeloid leukaemia (AML), and are in general associated with an unfavourable clinical outcome. Familial RUNX1 mutations are associated with familial thrombocytopenia and these patients have a predisposition to AML development. However, a number of studies have been performed so far in mice which might be distinct from the human hematopoietic system. Therefore we studied the cellular phenotypes, the RUNX1 binding pattern and expression profile induced by RUNX1mut in cord blood (CB) CD34+ cells and induced pluripotent stem cell (iPSC) and compared these findings to primary RUNX1mut AML’s.
2019-02-06 | GSE111918 | GEO
Project description:Mutations in the RUNX1 gene (RUNX1mut) have been established in myelodysplasia (MDS), de novo and secondary acute myeloid leukaemia (AML), and are in general associated with an unfavourable clinical outcome. Familial RUNX1 mutations are associated with familial thrombocytopenia and these patients have a predisposition to AML development. However, a number of studies have been performed so far in mice which might be distinct from the human hematopoietic system. Therefore we studied the cellular phenotypes, the RUNX1 binding pattern and expression profile induced by RUNX1mut in cord blood (CB) CD34+ cells and induced pluripotent stem cell (iPSC) and compared these findings to primary RUNX1mut AML’s.
2019-02-06 | GSE111917 | GEO
Project description:RUNX1 transcription factor (TF) is a key regulator of megakaryocytic development and when mutated is associated with familial platelet disorder and predisposition to acute myeloid leukemia (FPD-AML). We used mice lacking Runx1 specifically in megakaryocytes (MKs) to characterize the Runx1-mediated transcriptional program during advanced stages of MK differentiation. Gene expression and chromatin-immunoprecipitation-sequencing (ChIP-seq) of Runx1 and p300 identified functional Runx1-bound MK enhancers. Runx1/p300 co-bound regions showed significant enrichment in genes important for MK and platelet homeostasis. Runx1-bound regions were highly enriched in RUNX and ETS motifs and to a lesser extent in GATA motif. The data provides the first example of genome-wide Runx1/p300 occupancy in maturating FL-MK, unravels the Runx1-regulated program controlling MK maturation in vivo and identifies its bona fide regulated genes. It advances our understanding of the molecular events that upon mutations in RUNX1 lead to the predisposition to familial platelet disorders and FPD-AML. Gene expression profiles of mature megakaryocytes taken from fetal livers of megakaryocyte-specific Runx1 knockout mice, using Runx1F/F/Pf4-Cre mice versus control (WT) mice.
2013-03-22 | E-GEOD-45373 | biostudies-arrayexpress
Project description:RUNX1 transcription factor (TF) is a key regulator of megakaryocytic development and when mutated is associated with familial platelet disorder and predisposition to acute myeloid leukemia (FPD-AML). We used mice lacking Runx1 specifically in megakaryocytes (MKs) to characterize the Runx1-mediated transcriptional program during advanced stages of MK differentiation. Gene expression and chromatin-immunoprecipitation-sequencing (ChIP-seq) of Runx1 and p300 identified functional Runx1-bound MK enhancers. Runx1/p300 co-bound regions showed significant enrichment in genes important for MK and platelet homeostasis. Runx1-bound regions were highly enriched in RUNX and ETS motifs and to a lesser extent in GATA motif. The data provides the first example of genome-wide Runx1/p300 occupancy in maturating FL-MK, unravels the Runx1-regulated program controlling MK maturation in vivo and identifies its bona fide regulated genes. It advances our understanding of the molecular events that upon mutations in RUNX1 lead to the predisposition to familial platelet disorders and FPD-AML. Examination of RUNX1 and P300 binding in WT mouse megakaryoctye cells using ChIP-Seq. The supplementary 'GSE45372_PeakList.txt' file includes a list of regions identified as binding for P300 or RUNX1 or both.
2013-03-22 | E-GEOD-45372 | biostudies-arrayexpress
Project description:RUNX1 transcription factor (TF) is a key regulator of megakaryocytic development and when mutated is associated with familial platelet disorder and predisposition to acute myeloid leukemia (FPD-AML). We used mice lacking Runx1 specifically in megakaryocytes (MKs) to characterize the Runx1-mediated transcriptional program during advanced stages of MK differentiation. Gene expression and chromatin-immunoprecipitation-sequencing (ChIP-seq) of Runx1 and p300 identified functional Runx1-bound MK enhancers. Runx1/p300 co-bound regions showed significant enrichment in genes important for MK and platelet homeostasis. Runx1-bound regions were highly enriched in RUNX and ETS motifs and to a lesser extent in GATA motif. The data provides the first example of genome-wide Runx1/p300 occupancy in maturating FL-MK, unravels the Runx1-regulated program controlling MK maturation in vivo and identifies its bona fide regulated genes. It advances our understanding of the molecular events that upon mutations in RUNX1 lead to the predisposition to familial platelet disorders and FPD-AML.
2013-03-22 | GSE45373 | GEO
Project description:RUNX1 transcription factor (TF) is a key regulator of megakaryocytic development and when mutated is associated with familial platelet disorder and predisposition to acute myeloid leukemia (FPD-AML). We used mice lacking Runx1 specifically in megakaryocytes (MKs) to characterize the Runx1-mediated transcriptional program during advanced stages of MK differentiation. Gene expression and chromatin-immunoprecipitation-sequencing (ChIP-seq) of Runx1 and p300 identified functional Runx1-bound MK enhancers. Runx1/p300 co-bound regions showed significant enrichment in genes important for MK and platelet homeostasis. Runx1-bound regions were highly enriched in RUNX and ETS motifs and to a lesser extent in GATA motif. The data provides the first example of genome-wide Runx1/p300 occupancy in maturating FL-MK, unravels the Runx1-regulated program controlling MK maturation in vivo and identifies its bona fide regulated genes. It advances our understanding of the molecular events that upon mutations in RUNX1 lead to the predisposition to familial platelet disorders and FPD-AML.
2013-03-22 | GSE45372 | GEO
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