Role of transcriptional corepressor ETO2 in erythroid cells

Fujiwara, Tohru; Alqadi, Yarob Wael; Okitsu, Yoko; Fukuhara, Noriko; Onishi, Yasushi; Ishizawa, Kenichi; Harigae, Hideo

doi:10.1016/j.exphem.2012.10.015

Cited by 25 publications

(41 citation statements)

References 37 publications

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“…At molecular level, we found that TAL1s but not the TAL1fl loses the interaction with ETO2. Transcription corepressor ETO2 interacts with TAL1 and blocks early erythropoiesis [18, 19]. Consistently, we found that SF3B1 mutant blocks efficient erythroid differentiation, presumably by changing the ratio of TAL1s/TAL1fl in favor of TAL1fl.…”

Section: Introductionsupporting

confidence: 83%

“…To further understand the mechanism of TAL1s-mediated erythroipoiesis, we performed immunoprecipitation assays with the two different TAL1 isoforms. ETO2 has been shown to be involved in blocking early erythroid differentiation [18, 19, 21]. Our co-immunoprecipitation assay showed that TAL1s lost its interaction with ETO2 while TAL1fl binds to ETO2 as shown in 293T cells (Fig 3F) as well as in K562 cells (Fig 3G).…”

Section: Resultsmentioning

confidence: 53%

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Splicing factor SF3B1K700E mutant dysregulates erythroid differentiation via aberrant alternative splicing of transcription factor TAL1

Jin

Tran

et al. 2017

PLoS ONE

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More than 60% of myeloid dysplasia syndrome (MDS) contains mutations in genes encoding for splicing factors such as SF3B1, U2AF, SRSF2 and ZRSR2. Mutations in SF3B1 are associated with 80% cases of refractory anemia with ring sideroblast (RARS), a subtype of MDS. SF3B1K700E is the most frequently mutated site among mutations on SF3B1. Yet the molecular mechanisms on how mutations of splicing factors lead to defective erythropoiesis are not clear. SF3B1K700E mutant binds to an RNA binding protein, RBM15, stronger than the wild type SF3B1 protein in co-immunoprecipitation assays. In addition, K700E mutant alters the RNA splicing of transcription factors TAL1 and GATA1. Via alternative RNA splicing, a novel short TAL1 transcript variant (TAL1s) is generated. Enhanced interaction between SF3B1 and RBM15 promotes the production of full-length TAL1 (TAL1fl) mRNA, while reduction of RBM15 protein level via PRMT1-mediated degradation pathway changes TAL1s/TAL1fl ratio in favor of TAL1s. TAL1s contains the helix-loop-helix DNA binding domain but not the N terminal region upstream of the DNA binding domain. The TAL1s protein loses its interaction with ETO2, which represses early erythropoiesis. In this vein, overexpression of TAL1s stimulates the transcription of β-hemoglobin in human leukemia K562 cells and promotes erythroid differentiation of human cord blood CD34+ cells cultured in erythropoietin-containing medium. Therefore, mutations of SF3B1 may block erythropoiesis via dysregulation of alternative RNA splicing of transcription factor TAL1, and targeting PRMT1 may alleviate the anemic symptoms in MDS patients.

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Section: Introductionsupporting

confidence: 83%

Section: Resultsmentioning

confidence: 53%

Splicing factor SF3B1K700E mutant dysregulates erythroid differentiation via aberrant alternative splicing of transcription factor TAL1

Jin

Tran

et al. 2017

PLoS ONE

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“…On the other hand, the expression of GATA-1 was unaffected by LMO2 knockdown or hemin treatment ( Figure 1C). As a measure of erythroid maturation, we assessed the benzidine reactivity of the cells, which reflects the peroxidase activity of hemoglobin [23]. As shown in Figure 1D, hemin treatment significantly increased the percentages of benzidine-positive K562 cells under both control and LMO2 siRNA transfected conditions.…”

Section: K562 Cellsmentioning

confidence: 95%

“…We further investigated the role of LMO2 in human primary erythroblasts. Factor (SCF) (100 ng/mL), interleukin 3 (IL-3) (50 ng/mL), and granulocyte macrophage colony-stimulating factor (GM-CSF) (25 ng/mL), as described previously [23]. Subsequently, the CD34-positive cells were differentiated into erythroid cells with StemSpan SFEM (STEMCELL Technologies) containing 20 ng/mL SCF, 5 ng/mL IL-3, 1 U/mL erythropoietin (EPO), 2 µM dexamethasone (Sigma), and 1 µM β-estradiol for 12 days, as described previously [24].…”

Section: A N U S C R I P Tmentioning

confidence: 99%

“…Therefore, we moved to an ex vivo model of human erythroid differentiation, starting from G-CSF-mobilized peripheral blood-derived CD34-positive cells. As the number of CD34-positive cells available was too small for further functional analysis, isolated CD34-positive cells were first expanded in serum-free medium containing SCF, IL-3, and GM-CSF for 5 -7 days, as described previously [23], and subsequently underwent erythroid differentiation. Erythroid differentiation was evaluated by measuring the proportion of cell-surface CD71-and GPA-positive cells by FACS analysis ( Figure 7A).…”

Section: Lmo2 Expression In Cd34-positive Cell-derived Primary Erythrmentioning

confidence: 99%

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Elucidation of the role of LMO2 in human erythroid cells

Inoue

Fujiwara

Okitsu

et al. 2013

Experimental Hematology

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The ETO2 transcriptional cofactor maintains acute leukemia by driving a MYB/EP300‐dependent stemness program

Fagnan,

Aid,

Baille

et al. 2024

HemaSphere

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Transcriptional cofactors of the ETO family are recurrent fusion partners in acute leukemia. We characterized the ETO2 regulome by integrating transcriptomic and chromatin binding analyses in human erythroleukemia xenografts and controlled ETO2 depletion models. We demonstrate that beyond its well‐established repressive activity, ETO2 directly activates transcription of MYB, among other genes. The ETO2‐activated signature is associated with a poorer prognosis in erythroleukemia but also in other acute myeloid and lymphoid leukemia subtypes. Mechanistically, ETO2 colocalizes with EP300 and MYB at enhancers supporting the existence of an ETO2/MYB feedforward transcription activation loop (e.g., on MYB itself). Both small‐molecule and PROTAC‐mediated inhibition of EP300 acetyltransferases strongly reduced ETO2 protein, chromatin binding, and ETO2‐activated transcripts. Taken together, our data show that ETO2 positively enforces a leukemia maintenance program that is mediated in part by the MYB transcription factor and that relies on acetyltransferase cofactors to stabilize ETO2 scaffolding activity.

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Role of transcriptional corepressor ETO2 in erythroid cells

Cited by 25 publications

References 37 publications

Splicing factor SF3B1K700E mutant dysregulates erythroid differentiation via aberrant alternative splicing of transcription factor TAL1

Splicing factor SF3B1K700E mutant dysregulates erythroid differentiation via aberrant alternative splicing of transcription factor TAL1

Elucidation of the role of LMO2 in human erythroid cells

The ETO2 transcriptional cofactor maintains acute leukemia by driving a MYB/EP300‐dependent stemness program

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