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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE205437 | GEO | 2023/02/09

REPOSITORIES: GEO

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The NFIA-ETO2 fusion blocks erythroid maturation and induces pure erythroid leukemia in cooperation with mutant TP53.

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 the role for the pathogenesis of the disease, we facilitated the expression of the NFIA-ETO2 fusion in murine erythroblasts (EBs). We observed that NFIA-ETO2 significantly increased proliferation and impaired erythroid differentiation of murine erythroleukemia cells and of primary fetal liver-derived EBs. However, NFIA-ETO2-expressing EBs acquired neither aberrant in vitro clonogenic activity nor disease-inducing potential upon transplantation into irradiated syngenic mice. In contrast, in the presence of 1 of the most prevalent erythroleukemia-associated mutations, TP53R248Q, expression of NFIA-ETO2 resulted in aberrant clonogenic activity and induced a fully penetrant transplantable PEL-like disease in mice. Molecular studies support that NFIA-ETO2 interferes with erythroid differentiation by preferentially binding and repressing erythroid genes that contain NFI binding sites and/or are decorated by ETO2, resulting in a activity shift from GATA- to ETS-motif-containing target genes. In contrast, TP53R248Q does not affect erythroid differentiation but provides self-renewal and survival potential, mostly via downregulation of known TP53 targets. Collectively, our work indicates that NFIA-ETO2 initiates PEL by suppressing gene expression programs of terminal erythroid differentiation and cooperates with TP53 mutation to induce erythroleukemia.

| S-EPMC10646783 | biostudies-literature

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

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 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)

2023-02-09 | GSE205420 | GEO

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

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

Project description:The NFIA-ETO2 fusion blocks terminal erythroid maturation and induces pure erythroid leukemia in cooperation with mutant TP53

| PRJNA845219 | ENA

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

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

| PRJNA844994 | ENA

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

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

| PRJNA844961 | ENA

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

2023-02-09 | GSE205407 | GEO

Down-regulation of Myc is essential for terminal erythroid maturation.

Project description:Terminal differentiation of mammalian erythroid progenitors involves 4-5 cell divisions and induction of many erythroid important genes followed by chromatin and nuclear condensation and enucleation. The protein levels of c-Myc (Myc) are reduced dramatically during late stage erythroid maturation, coinciding with cell cycle arrest in G(1) phase and enucleation, suggesting possible roles for c-Myc in either or both of these processes. Here we demonstrate that ectopic Myc expression affects terminal erythroid maturation in a dose-dependent manner. Expression of Myc at physiological levels did not affect erythroid differentiation or cell cycle shutdown but specifically blocked erythroid nuclear condensation and enucleation. Continued Myc expression prevented deacetylation of several lysine residues in histones H3 and H4 that are normally deacetylated during erythroid maturation. The histone acetyltransferase Gcn5 was up-regulated by Myc, and ectopic Gcn5 expression partially blocked enucleation and inhibited the late stage erythroid nuclear condensation and histone deacetylation. When overexpressed at levels higher than the physiological range, Myc blocked erythroid differentiation, and the cells continued to proliferate in cytokine-free, serum-containing culture medium with an early erythroblast morphology. Gene expression analysis demonstrated the dysregulation of erythropoietin signaling pathway and the up-regulation of several positive regulators of G(1)-S cell cycle checkpoint by supraphysiological levels of Myc. These results reveal an important dose-dependent function of Myc in regulating terminal maturation in mammalian erythroid cells.

| S-EPMC3001006 | biostudies-literature

FOXO3-mTOR metabolic cooperation in the regulation of erythroid cell maturation and homeostasis.

Project description:Ineffective erythropoiesis is observed in many erythroid disorders including ?-thalassemia and anemia of chronic disease in which increased production of erythroblasts that fail to mature exacerbate the underlying anemias. As loss of the transcription factor FOXO3 results in erythroblast abnormalities similar to the ones observed in ineffective erythropoiesis, we investigated the underlying mechanisms of the defective Foxo3(-/-) erythroblast cell cycle and maturation. Here we show that loss of Foxo3 results in overactivation of the JAK2/AKT/mTOR signaling pathway in primary bone marrow erythroblasts partly mediated by redox modulation. We further show that hyperactivation of mTOR signaling interferes with cell cycle progression in Foxo3 mutant erythroblasts. Importantly, inhibition of mTOR signaling, in vivo or in vitro enhances significantly Foxo3 mutant erythroid cell maturation. Similarly, in vivo inhibition of mTOR remarkably improves erythroid cell maturation and anemia in a model of ?-thalassemia. Finally we show that FOXO3 and mTOR are likely part of a larger metabolic network in erythroblasts as together they control the expression of an array of metabolic genes some of which are implicated in erythroid disorders. These combined findings indicate that a metabolism-mediated regulatory network centered by FOXO3 and mTOR control the balanced production and maturation of erythroid cells. They also highlight physiological interactions between these proteins in regulating erythroblast energy. Our results indicate that alteration in the function of this network might be implicated in the pathogenesis of ineffective erythropoiesis.

| S-EPMC4201594 | biostudies-literature

Characterization of megakaryocyte GATA1-interacting proteins: the corepressor ETO2 and GATA1 interact to regulate terminal megakaryocyte maturation.

Project description:The transcription factor GATA1 coordinates timely activation and repression of megakaryocyte gene expression. Loss of GATA1 function results in excessive megakaryocyte proliferation and disordered terminal platelet maturation, leading to thrombocytopenia and leukemia in patients. The mechanisms by which GATA1 does this are unclear. We have used in vivo biotinylated GATA1 to isolate megakaryocyte GATA1-partner proteins. Here, several independent approaches show that GATA1 interacts with several proteins in the megakaryocyte cell line L8057 and in primary megakaryocytes. They include FOG1, the NURD complex, the pentameric complex containing SCL/TAL-1, the zinc-finger regulators GFI1B and ZFP143, and the corepressor ETO2. Knockdown of ETO2 expression promotes megakaryocyte differentiation and enhances expression of select genes expressed in terminal megakaryocyte maturation, eg, platelet factor 4 (Pf4). ETO2-dependent direct repression of the Pf4 proximal promoter is mediated by GATA-binding sites and an E-Box motif. Consistent with this, endogenous ETO2, GATA1, and the SCL pentameric complex all specifically bind the promoter in vivo. Finally, as ETO2 expression is restricted to immature megakaryocytes, these data suggest that ETO2 directly represses inappropriate early expression of a subset of terminally expressed megakaryocyte genes by binding to GATA1 and SCL.

| S-EPMC2556610 | biostudies-literature

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