The Gata1 murine megakaryocyte–erythroid progenitor cells expand robustly and alter differentiation potential

Shin, Eunju; Jeong, Jong-Gwan; Chung, Hyunmin; Jung, Hye Young; Park, Charny; Yoon, Suk Ran; Kim, Tae-Don; Lee, Seung Jin; Choi, Inpyo; Noh, Ji-Yoon

doi:10.1016/j.bbrc.2020.04.143

Cited by 4 publications

(5 citation statements)

References 29 publications

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“…Although we cannot formally exclude impaired expression of CD41 and CD42a in MKs harboring a GATA1 variant, the reduction in high-ploidy cells confirmed the MK maturation defect.Additionally, the GATA1 N206I carrier displayed an increase in circulating CD34+ progenitor cells, as described for individuals carrying a germline ETV6 variants 37. Recently, Shin et al38 have found Identification and functional analysis of the MYH10 regulatory regions. A, Visualization of MYH10 regulatory regions with GATA1, FLI1, and RUNX1 binding peaks identified via chromatin immunoprecipitation-sequencing.…”

mentioning

confidence: 73%

“…There are substantial developmental differences between neonates and adults in the process of megakaryopoiesis and in their responses to TPO 35 . Wenqing and colleagues have highlighted fundamental and conserved differences at distinct developmental stages, characterized by simpler promoter‐centric regulation of cell‐type‐specific genes in embryonic cells and increased combinatorial enhancer‐driven control in adult cells 36 . Overall, the delayed onset of thrombocytopenia observed in the F2 family suggest developmental stage‐specific GATA‐1 regulation.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, the GATA1 N206I carrier displayed an increase in circulating CD34+ progenitor cells, as described for individuals carrying a germline ETV6 variants. 37 Recently, Shin et al 38 have found that Gata1 low megakaryocyte-erythroid progenitors/megakaryocyte precursors cell lines display accelerated replication after approximately 90 to 100 days of culture. The observed increase in CD34+ cells may reflect this high proliferative capacity.…”

Section: Discussionmentioning

confidence: 99%

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GATA1 pathogenic variants disrupt MYH10 silencing during megakaryopoiesis

Saultier

Cabantous

Pucéat

et al. 2021

Journal of Thrombosis and Haemostasis

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Background: GATA1 is an essential transcription factor for both polyploidization and megakaryocyte (MK) differentiation. The polyploidization defect observed in GATA1 variant carriers is not well understood.Objective: To extensively phenotype two pedigrees displaying different variants in the GATA1 gene and determine if GATA1 controls MYH10 expression levels, a key modulator of MK polyploidization.Method: A total of 146 unrelated propositi with constitutional thrombocytopenia were screened on a multigene panel. We described the genotype-phenotype correlation in GATA1 variant carriers and investigated the effect of these novel variants on MYH10 transcription using luciferase constructs. Results:The clinical profile associated with the p.L268M variant localized in the C terminal zinc finger was unusual in that the patient displayed bleeding and severe platelet aggregation defects without early-onset thrombocytopenia. p.N206I localized in the N terminal zinc finger was associated, on the other hand, with severe thrombocytopenia (15G/L) in early life. High MYH10 levels were evidenced in platelets of GATA1 variant carriers. Analysis of MKs anti-GATA1 chromatin immunoprecipitation-sequencing data revealed two GATA1 binding sites, located in the 3′ untranslated region and in intron 8 of the MYH10 gene. Luciferase reporter assays showed their respective role in the regulation of MYH10 gene expression. Both GATA1 variants significantly alter intron 8 driven MYH10 transcription. Conclusion:The discovery of an association between MYH10 and GATA1 is a novel one. Overall, this study suggests that impaired MYH10 silencing via an intronic regulatory element is the most likely cause of GATA1-related polyploidization defect.

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confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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GATA1 pathogenic variants disrupt MYH10 silencing during megakaryopoiesis

Saultier

Cabantous

Pucéat

et al. 2021

Journal of Thrombosis and Haemostasis

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“…CD117 CAR-T cells were recently reported to efficiently eliminate AML blasts as well as CD117 + healthy HSCs in the AML model [81]. CD117, a receptor tyrosine kinase to which stem cell factor binds, is expressed on hematopoietic precursors; however, it may remain overexpressed following malignant transformation in HSCs [82,83]. In a recent study, the CAR was modified to comprise an anti-CLL-1 scFv linked to an anti-CD33 scFv via a self-cleaving P2A peptide, resulting in the expression of both functional CARs on the T cell surface [84].…”

Section: Immunotherapy For Amlmentioning

confidence: 99%

Immunotherapy in Hematologic Malignancies: Emerging Therapies and Novel Approaches

Noh

Seo

Lee

et al. 2020

IJMS

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Immunotherapy is extensively investigated for almost all types of hematologic tumors, from preleukemic to relapse/refractory malignancies. Due to the emergence of technologies for target cell characterization, antibody design and manufacturing, as well as genome editing, immunotherapies including gene and cell therapies are becoming increasingly elaborate and diversified. Understanding the tumor immune microenvironment of the target disease is critical, as is reducing toxicity. Although there have been many successes and newly FDA-approved immunotherapies for hematologic malignancies, we have learned that insufficient efficacy due to disease relapse following treatment is one of the key obstacles for developing successful therapeutic regimens. Thus, combination therapies are also being explored. In this review, immunotherapies for each type of hematologic malignancy will be introduced, and novel targets that are under investigation will be described.

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“…The inhibition of HDAC activity resulted in the transcriptional activation of genes that participated in hematopoietic differentiation, including CEBPA and PU.1, the regulators of granulocytic differentiation 28,29 (Figure 3C and D), and GATA1, (Figure 3E) the master transcription factor of megakaryopoiesis and erythropoiesis. 30,31 Oral Administered ee-As 4 S 4 Induced Differentiation and Apoptosis of Leukemic Cells in AML Mice…”

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confidence: 99%

Hydrophilic Realgar Nanocrystals Prolong the Survival of Refractory Acute Myeloid Leukemia Mice Through Inducing Multi-Lineage Differentiation and Apoptosis

Wang¹,

Zhang²,

Jia³

et al. 2022

IJN

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Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic progenitor cells, and the AML cells are differentiation retarded which results in the hyperproliferation of those malignant tumor cells. To stop the uncontrollable proliferation, inducing the AML cell differentiation is one highly expected therapy because it can bring relatively low systematic side effects compared to conventional chemotherapies; however, there are few options of inductive therapeutics in the clinical applications so far. This study aims to investigate the differentiation-induction effects of lab-developed hydrophilic nanocrystals of As 4 S 4 (ee-As 4 S 4 ). Methods: In this work, ee-As 4 S 4 was applied upon a refractory mouse model co-expressing AML1-ETO and HyC-KIT D816V as well as a related human AML cell line, Kasumi-1, to investigate whether the nanocrystals can break the retardation of differentiation and drive the cells undergo apoptosis. Results: It was shown that ee-As 4 S 4 induced the upregulation of surface markers CD11b, CD235a, and CD41a, which indicate granulocytic, erythroid, and megakaryocytic differentiation respectively, leading to the multiple-lineage differentiation and postdifferentiation apoptosis, and the inhibition of histone deacetylase activity was largely involved with the differentiation-induction effects. In the AML mice, orally administered ee-As 4 S 4 increased the level of Ter119, CD11b, and CD41 in bone marrow-derived leukemia cells while reducing the percentage of leukemic cells in the bone marrow. Also, ee-As 4 S 4 improved the hemogram and relieved the hepatomegaly and splenomegaly of the AML mice. As a result, the survival of the AML mice was significantly prolonged. Importantly, ee-As 4 S 4 did not cause acute or chronic toxicity in healthy mice. Conclusion:In conclusion, ee-As 4 S 4 induced effective and multiple-lineage differentiation and apoptosis of AML cells in the refractory AML mouse model and cell line, suggesting that it holds promising potential as a novel inductive agent in differentiation therapy of AML.

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The Gata1 murine megakaryocyte–erythroid progenitor cells expand robustly and alter differentiation potential

Cited by 4 publications

References 29 publications

GATA1 pathogenic variants disrupt MYH10 silencing during megakaryopoiesis

GATA1 pathogenic variants disrupt MYH10 silencing during megakaryopoiesis

Immunotherapy in Hematologic Malignancies: Emerging Therapies and Novel Approaches

Hydrophilic Realgar Nanocrystals Prolong the Survival of Refractory Acute Myeloid Leukemia Mice Through Inducing Multi-Lineage Differentiation and Apoptosis

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