Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay

Juban, Gaëtan; Sakakini, Nathalie; Chagraoui, Hédia; Hernandez, David Cruz; Cheng, Qian; Soady, Kelly; Stoilova, Bilyana; Garnett, Catherine; Waithe, Dominic; Otto, G.; Doondeea, Jessica; Usukhbayar, Batchimeg; Karkoulia, Elena; Alexiou, Maria; Strouboulis, John; Morrissey, Edward; Roberts, Irene; Porcher, Catherine; Vyas, Paresh

doi:10.3324/haematol.2019.244541

Cited by 11 publications

(7 citation statements)

References 32 publications

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“…Megakaryocytes are detected in the yolk sac at E9.5 and circulating platelets have been identified in murine embryonic vasculature at E10.5 38 . CD42b + cells have also been identified in the yolk sac at E10.5, indicating expression of GPIbα at this time point 39 . The ability of the pTFPIα Tg to rescue lethality during mid‐gestation suggests a potential role for TFPIα that is specific for fetal platelets because the Tg was not present in the Tfpi +/− maternal genome.…”

Section: Discussionmentioning

confidence: 99%

“…38 CD42b + cells have also been identified in the yolk sac at E10.5, indicating expression of GPIbα at this time point. 39 The ability of the pTFPIα Tg to rescue lethality during mid-gestation suggests a potential role for TFPIα that is specific for fetal platelets because the Tg was not present in the Tfpi +/− maternal genome. However, p45NF-E2 knockout mice with severe thrombocytopenia survive to birth, 40 indicating that fetal platelets are dispensable for placentation.…”

Section: Discussionmentioning

confidence: 99%

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Intrauterine lethality in Tfpi gene disrupted mice is differentially suppressed during mid‐ and late‐gestation by platelet TFPIα overexpression

Siebert

Maroney

Martinez

et al. 2021

Journal of Thrombosis and Haemostasis

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Background: Tissue factor pathway inhibitor (TFPI) is an anticoagulant protein required for murine embryonic development. Intrauterine lethality of Tfpi −/− mice occurs at mid-and late gestation, the latter of which is associated with severe cerebrovascular defects. Megakaryocytes produce only the TFPIα isoform, which is stored within platelets and released upon activation.Objectives: To examine biological activities of platelet TFPIα (pTFPIα) by characterizing effects of pTFPIα overexpression in Tfpi −/− mice.Methods: Transgenic mice overexpressing pTFPIα were generated and crossed onto the Tfpi −/− background. Genetic and histological analyses of embryos were performed to investigate the function of pTFPIα during embryogenesis. Results:The transgene (Tg) increased pTFPIα 4-to 5-fold without altering plasma TFPI in adult Tfpi +/+ and Tfpi +/− mice but did not rescue Tfpi −/− mice to wean. Analyses of the impact of pTFPIα overexpression on Tfpi −/− survival, however, were complicated by linkage between the Tg integration site and the endogenous Tfpi locus on chromosome 2. Strain-specific genetic interactions also modulated Tfpi −/− embryonic survival. After accounting for these underlying genetic factors, pTFPIα overexpression completely suppressed mid-gestational lethality of Tfpi −/− embryos but had no effect on development of cerebrovascular defects during late gestation resulting in their lack of survival to wean.Conclusions: pTFPIα overexpression rescued Tfpi −/− embryos from mid-gestational but not late gestational lethality. The prevalence of underlying genetic factors complicating analyses within our study illustrates the importance of meticulously characterizing transgenic mouse models to avoid spurious interpretation of results.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Intrauterine lethality in Tfpi gene disrupted mice is differentially suppressed during mid‐ and late‐gestation by platelet TFPIα overexpression

Siebert

Maroney

Martinez

et al. 2021

Journal of Thrombosis and Haemostasis

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“…RUNX1a (also known as AML1a), a C-terminally truncated RUNX1 isoform, increases DNA binding and affects target gene transcription, with its overexpression increasing functional HSCs and decreasing hematopoietic differentiation ( Davis et al, 2021 ). GATA1s, an N-terminally truncated GATA1 isoform, plays a major role in transient abnormal myelopoiesis and ML-DS development by promoting megakaryocytic progenitor expansion and disrupting megakaryocytic and erythroid differentiation ( Wechsler et al, 2002 ; Shimizu et al, 2009 ; Chlon et al, 2015 ; Banno et al, 2016 ; Juban et al, 2021 ). The c-MYC proto-oncogene was discovered as a target of RBM15 during HSC and megakaryocyte development ( Niu et al, 2009 ).…”

Section: Molecular Characterization Of Pediatric Non-ds Amklmentioning

confidence: 99%

Advances in molecular characterization of pediatric acute megakaryoblastic leukemia not associated with Down syndrome; impact on therapy development

Kalev‐Zylinska

2023

Front. Cell Dev. Biol.

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Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia (AML) in which leukemic blasts have megakaryocytic features. AMKL makes up 4%–15% of newly diagnosed pediatric AML, typically affecting young children (less than 2 years old). AMKL associated with Down syndrome (DS) shows GATA1 mutations and has a favorable prognosis. In contrast, AMKL in children without DS is often associated with recurrent and mutually exclusive chimeric fusion genes and has an unfavorable prognosis. This review mainly summarizes the unique features of pediatric non-DS AMKL and highlights the development of novel therapies for high-risk patients. Due to the rarity of pediatric AMKL, large-scale multi-center studies are needed to progress molecular characterization of this disease. Better disease models are also required to test leukemogenic mechanisms and emerging therapies.

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“…Two recent studies in murine embryonic stem cells (ES) and human T21 iPSCs narrowed down the search for the cellular origin of TAM to a population of immature megakaryocytic progenitors characterized by high CD41 expression ( 108 , 109 ). During step-wise hematopoiesis in vitro , these cells showed delayed and aberrant megakaryocytic differentiation, reduced erythroid differentiation and gave rise to an increased number of myeloid cells upon GATA1s expression ( 108 , 109 ).…”

Section: Development Of Tam: the Role Of Gata1s In Ds Leukemogenesismentioning

confidence: 99%

Molecular Mechanisms of the Genetic Predisposition to Acute Megakaryoblastic Leukemia in Infants With Down Syndrome

2021

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Individuals with Down syndrome are genetically predisposed to developing acute megakaryoblastic leukemia. This myeloid leukemia associated with Down syndrome (ML–DS) demonstrates a model of step-wise leukemogenesis with perturbed hematopoiesis already presenting in utero, facilitating the acquisition of additional driver mutations such as truncating GATA1 variants, which are pathognomonic to the disease. Consequently, the affected individuals suffer from a transient abnormal myelopoiesis (TAM)—a pre-leukemic state preceding the progression to ML–DS. In our review, we focus on the molecular mechanisms of the different steps of clonal evolution in Down syndrome leukemogenesis, and aim to provide a comprehensive view on the complex interplay between gene dosage imbalances, GATA1 mutations and somatic mutations affecting JAK-STAT signaling, the cohesin complex and epigenetic regulators.

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Oncogenic Gata1 causes stage-specific megakaryocyte differentiation delay

Abstract: GATA1s-induced stage-specific differentiation delay increases immature megakaryocytes in vivo and in vitro, during development. Differentiation delay is associated with increased numbers of cells in S-phase and reduced apoptosis.

Cited by 11 publications

References 32 publications

Intrauterine lethality in Tfpi gene disrupted mice is differentially suppressed during mid‐ and late‐gestation by platelet TFPIα overexpression

Intrauterine lethality in Tfpi gene disrupted mice is differentially suppressed during mid‐ and late‐gestation by platelet TFPIα overexpression

Advances in molecular characterization of pediatric acute megakaryoblastic leukemia not associated with Down syndrome; impact on therapy development

Molecular Mechanisms of the Genetic Predisposition to Acute Megakaryoblastic Leukemia in Infants With Down Syndrome

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