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The NFIA-ETO2 fusion blocks terminal erythroid maturation and induces pure erythroid leukemia (PEL) in cooperation with mutant TP53

ABSTRACT: The NFIA-ETO2 fusion is the product of a t(1;16)(p31;q24) chromosomal translocation so far exclusively found in pediatric patients with pure erythroid leukemia (PEL). To address its role for the pathogenesis of the pure erythroid leukemia, we retrovirally expressed the PEL-associated NFIA-ETO2 fusion or an in active NFIA-ETOdeltaNHR4 mutant in primary erythroblasts in fetal liver-derived erythroblasts from either wild-type (C57/B6) or TP53R248Q (HUPKI) mice. Gene expression was determined by RNA sequencing from cells kept in maintenance medium (MM) or 24h in differentiation-inducing medium (DM)

ORGANISM(S): Mus musculus

PROVIDER: GSE205420 | GEO | 2023/02/09

REPOSITORIES: GEO

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The NFIA-ETO2 fusion blocks terminal erythroid maturation and induces pure erythroid leukemia (PEL)

Project description:The NFIA-ETO2 fusion is the product of a t(1;16)(p31;q24) chromosomal translocation so far exclusively found in pediatric patients with pure erythroid leukemia (PEL). To address its role for the pathogenesis of the pure erythroid leukemia, we retrovirally expressed the PEL-associated NFIA-ETO2 fusion in primary erythroblasts in fetal liver-derived erythroblasts from wild-type (C57/B6) mice. To better characterize alteration in chromatin accessibility due to NFIA-ETO2 expression, we analyzed accessible chromatin state by ATAC sequencing from cells kept in 24h in differentiation-inducing medium (DM)

2023-02-08 | GSE205392 | GEO

Effect of NFIA-ETO2 gene fusion on MEL cells during proliferation and impaired erythroid differentiation.

2023-02-09 | GSE205407 | GEO

Location of NFIA-ETO2 binding site on genome in MEL cells

Project description:The NFIA-ETO2 fusion is the product of a t(1;16)(p31;q24) chromosomal translocation so far exclusively found in pediatric patients with pure erythroid leukemia (PEL). To address its role for the pathogenesis of the pure erythroid leukemia, we retrovirally expressed the PEL-associated NFIA-ETO2 fusion in MEL cells. To better identify direct target gene loci, we sequenced NFIA-ETO2-associated immunoprecipitated chromatin and histone modifications.

2023-02-09 | GSE205397 | GEO

Inactivation of the nuclear interacting SET domain protein 1 (NSD1) impairs GATA1-regulated erythroid differentiation and causes erythroleukemia

Project description:Nuclear receptor binding SET domain protein 1 (NSD1) is recurrently mutated in human cancers including acute leukemia. We found that NSD1 knockdown altered erythroid clonogenic growth of human CD34+ hematopoietic cells. Ablation of Nsd1 in the hematopoietic system induced a transplantable erythroleukemia in mice. Despite abundant expression of the transcriptional master regulator GATA1, in vitro differentiation of Nsd1-/- erythroblasts was majorly impaired associated with reduced activation of GATA1-induced targets, while GATA1-repressed target genes were less affected. Retroviral expression of wildtype Nsd1, but not a catalytically-inactive Nsd1N1918Q SET-domain mutant induced terminal maturation of Nsd1-/- erythroblasts. Despite similar GATA1 levels, exogenous Nsd1 but not Nsd1N1918Q significantly increased GATA1 chromatin occupancy and target gene activation. Notably, Nsd1 expression reduced the association of GATA1 with the co-repressor SKI, and knockdown of SKI induced differentiation of Nsd1-/- erythroblasts. Collectively, we identified the NSD1 methyltransferase as a novel regulator of GATA1-controlled erythroid differentiation and leukemogenesis.

2020-04-08 | PXD017657 | Pride

Global Transcriptome Analyses of Mammalian Terminal Erythroid Differentiation

Project description:Purpose:The purpose of this study is to create unbiased, stage-specific transcriptomes by RNA-seq analyses of pure populations of both murine and human erythroblasts at distinct developmental stages. Methods: Recently developed FACS-based methods (Chen et al, PNAS, Liu et al, Blood, Hu et al Blood) were employed to purify morphologically and functionally discrete populations of cells, each representing specific stages of terminal erythroid differentiation. RNA was prepared from these cells and subjected to RNA-seq analyses. Results: There were vast temporal changes in gene expression across the differentiation stages, with each stage exhibiting unique transcriptomes.Clustering and network analyses revealed that differing stage-specific patterns of expression across differentiation were transcriptionally enriched for genes of differing function. Numerous differences were present between human and murine transcriptomes, with significant variation in the global patterns of gene expression. Conclusions: These data provide a significant resource for studies of normal and perturbed erythropoiesis, allowing a deeper understanding of mechanisms of erythroid development, differentiation, and inherited and acquired disease. Both murine and human erythroblasts at distinct developmental stage mRNA profiles were generated by deep sequencing, in triplicate, using IlluminaHiSeq 2000.

2014-03-19 | E-GEOD-53983 | biostudies-arrayexpress

Single-cell multiomics reveals stage of differentiation and trajectory-dependent immunity-related gene expression patterns in human erythroid cells

Project description:Erythroid cells, serving as progenitors and precursors to erythrocytes responsible for oxygen transport, exhibit a notable immunosuppressive and immunoregulatory phenotype. The present study CITE-seq reveals that erythroid cells have stage of differentiation-dependent immunity-related gene expression patterns. We also found that Erythroid cell differentiation is not linear and there is a bifurcation of polychromatophilic erythroblasts into ARG1 expressing polychromatophilic erythroblasts and orthochromatophilic erythroblasts. ARG1 expressing polychromatophilic erythroblasts account for almost all immunosuppressive ARG1 gene expression among erythroid cells. Thus, we infer the stepwise erythroid cells differentiation trajectory that has a branch that forms immunosuppressive erythroid cell population.

2024-03-20 | GSE261733 | GEO

Transglutaminase 2 regulates terminal erythroid differentiation via cross-linking activity

Project description:To gain the whole picture of terminal erythroid differentiation, bone marrow erythroblasts of different maturation stages including proerythroblasts (Pro),basophilic erythroblasts (Baso), polychromatic erythroblasts (Poly) and orthochromatic erythroblasts (Ortho) were isolated and sorted.Transcriptomic analysis of these four stages of cells was performed.

2023-04-23 | GSE229589 | GEO

Control of developmentally primed erythroid genes by combinatorial corepressor actions

Project description:How transcription factors (TFs) cooperate within large protein complexes to allow rapid modulation of gene expression during development is still largely unknown. Here we show that the key haematopoietic LIM-domain-binding protein-1 (LDB1) TF complex contains several activator and repressor components that together maintain an erythroid-specific gene expression programme primed for rapid activation until differentiation is induced. A combination of proteomics, functional genomics and in vivo studies presented here identifies known and novel co-repressors, most notably the ETO2 and IRF2BP2 proteins, involved in maintaining this primed state. The ETO2â??IRF2BP2 axis, interacting with the NCOR1/SMRT co-repressor complex, suppresses the expression of the vast majority of archetypical erythroid genes and pathways until its decommissioning at the onset of terminal erythroid differentiation. Our experiments demonstrate that multimeric regulatory complexes feature a dynamic interplay between activating and repressing components that determines lineage-specific gene expression and cellular differentiation. ChIP-Sequencing profiles of the IRF2BP2, GFI1B and LSD1 proteins were generated using mouse erythroleukemia (MEL) cells. RNA-seq experiments of Irf2bp2-WT, Irf2bp2-KD, Eto2-WT, Eto2-KD, Gfi1b-WT, Gfi1b-KD, Lsd1-WT, Lsd1-KD, MEL-non-induced, and MEL-induced stages were performed using standard RNA-seq protocol. Illumina HiSeq 2000 (standard TruSeq RNA sequencing protocol) was used for the sequencing.

2015-11-19 | E-GEOD-59859 | biostudies-arrayexpress

Control of developmentally primed erythroid genes by combinatorial corepressor actions

Project description:How transcription factors (TFs) cooperate within large protein complexes to allow rapid modulation of gene expression during development is still largely unknown. Here we show that the key haematopoietic LIM-domain-binding protein-1 (LDB1) TF complex contains several activator and repressor components that together maintain an erythroid-specific gene expression programme primed for rapid activation until differentiation is induced. A combination of proteomics, functional genomics and in vivo studies presented here identifies known and novel co-repressors, most notably the ETO2 and IRF2BP2 proteins, involved in maintaining this primed state. The ETO2–IRF2BP2 axis, interacting with the NCOR1/SMRT co-repressor complex, suppresses the expression of the vast majority of archetypical erythroid genes and pathways until its decommissioning at the onset of terminal erythroid differentiation. Our experiments demonstrate that multimeric regulatory complexes feature a dynamic interplay between activating and repressing components that determines lineage-specific gene expression and cellular differentiation.

2015-11-19 | GSE59859 | GEO

Induction of S100A8/S100A9 mediates the erythroid differentiation block in ribosomal protein S14 haploinsufficiency

Project description:Schneider RK, Schenone M, Kramann R, Ferreira MV, Joyce CE, Hartigan C, Beier F, Brümmendorf TH, Gehrming U, Platzbecker U, Buesche G, Chen MC, Waters CS, Chen E, Chu LP, Novina CD, Lindsley RC, Carr SA, Ebert BL. Nat Med, 2016. Heterozygous deletion of RPS14 occurs in del(5q) MDS and has been linked to impaired erythropoiesis, characteristic of this disease subtype. We generated a murine model with conditional inactivation of Rps14 and demonstrated a p53-dependent erythroid differentiation defect with apoptosis at the transition from polychromatic to orthochromatic erythroblasts resulting in age-dependent progressive anemia, megakaryocyte dysplasia, and loss of hematopoietic stem cell (HSC) quiescence. Using quantitative proteomics, we identified significantly increased expression of proteins involved in innate immune signaling, particularly the heterodimeric S100A8/S100A9 proteins in purified erythroblasts. S100A8 expression was significantly increased in erythroblasts, monocytes and macrophages and recombinant S100A8 was sufficient to induce an erythroid differentiation defect in wild-type cells. We rescued the erythroid differentiation defect in Rps14 haploinsufficient HSCs by genetic inactivation of S100a8 expression. Our data link Rps14 haploinsufficiency to activation of the innate immune system via induction of S100A8/A9 and the p53-dependant erythroid differentiation defect in del(5q) MDS.

2016-01-26 | MSV000079482 | MassIVE

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