Paris-Trousseau: evidence keeps pointing to FLI1

Paola, Jorge Di

doi:10.1182/blood-2015-09-667634

Cited by 4 publications

(6 citation statements)

References 9 publications

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“…45 Patients with PTS typically have an increased bleeding tendency of variable severity. 10,42,48 Platelet function abnormalities in α- and dense secretion in response to thrombin have been observed. 10,46 …”

Section: Fli1mentioning

confidence: 99%

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Inherited platelet dysfunction and hematopoietic transcription factor mutations

Songdej

Rao

2016

Platelets

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Transcription factors (TF) are proteins that bind to specific DNA sequences and regulate expression of genes. The molecular and genetic mechanisms in most patients with inherited platelet dysfunction are unknown. There is now increasing evidence that mutations in hematopoietic TFs are an important underlying cause for defects in platelet production, morphology, and function. The hematopoietic TFs implicated in patients with impaired platelet function include runt related transcription factor 1 (RUNX1), Fli-1 proto-oncogene, ETS transcription factor (FLI1), GATA-binding protein 1 (GATA1), and growth factor independent 1B transcriptional repressor (GFI1B). These TFs act in a combinatorial manner to bind sequence-specific DNA within a promoter region to regulate lineage-specific gene expression, either as activators or repressors. TF mutations induce rippling downstream effects by simultaneously altering the expression of multiple genes. Mutations involving these transcription factors affect diverse aspects of megakaryocyte biology, and platelet production and function, culminating in thrombocytopenia, platelet dysfunction, and associated clinical features. Mutations in TFs may occur more frequently in patients with inherited platelet dysfunction than generally appreciated. This review focuses on the alterations in hematopoietic TFs in the pathobiology of inherited platelet dysfunction.

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Section: Fli1mentioning

confidence: 99%

“…The normal platelet count and function of the parents with heterozygous FLI1 mutation also suggests that the mechanisms by which FLI1 alterations produce abnormalities in megakaryopoiesis and platelet function remain to be elucidated. 48 …”

Section: Fli1mentioning

confidence: 99%

Inherited platelet dysfunction and hematopoietic transcription factor mutations

Songdej

Rao

2016

Platelets

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“…Indeed, targeting Fli‐1 during embryogenesis results in early lethality associated with severe defect in hematopoiesis and vasculogenesis . Hemizygous loss of Fli‐1 function is the main cause of thrombocytopenia in patients with Paris Trousseau syndrome . Fli‐1 expression is also critical for B‐cell development and its overexpression promotes autoimmune Lupus in mice .…”

Section: Introductionmentioning

confidence: 99%

Novel flavagline‐like compounds with potent Fli‐1 inhibitory activity suppress diverse types of leukemia

et al. 2018

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E26 transformation‐specific (ETS) gene family contains a common DNA‐binding domain, the ETS domain, responsible for sequence‐specific DNA recognition on target promoters. The Fli‐1 oncogene, a member of ETS gene family, plays a critical role in hematopoiesis and is overexpressed in diverse hematological malignancies. This ETS transcription factor regulates genes controlling several hallmarks of cancer and thus represents an excellent target for cancer therapy. By screening compounds isolated from the medicinal plant Dysoxylum binectariferum in China, we identified two chemically related flavagline‐like compounds including 4′‐demethoxy‐3′,4′‐methylenedioxyrocaglaol and rocaglaol that strongly inhibited Fli‐1 transactivation ability. These compounds altered expression of Fli‐1 target genes including GATA1, EKLF, SHIP1, and BCL2. Consequently, the flavagline‐like compounds suppressed proliferation, induced apoptosis, and promoted erythroid differentiation of leukemic cells in culture. These compounds also suppressed erythroleukemogenesis in vivo in a Fli‐1‐driven mouse model. Mechanistically, the compounds blocked c‐Raf‐MEK‐MAPK/ERK signaling, reduced phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), and inhibited Fli‐1 protein synthesis. Consistent with its high expression in myelomas, B‐cell lymphoma, and B chronic lymphocytic leukemia (B‐CLL), pharmacological inhibition of Fli‐1 by the flavagline‐like compounds or genetic knock‐down via shRNA significantly hindered proliferation of corresponding cell lines and patients’ samples. These results uncover a critical role of Fli‐1 in growth and survival of various hematological malignancies and point to flavagline‐like agents as lead compounds for the development of anti‐Fli‐1 drugs to treat leukemias/lymphomas overexpressing Fli‐1.

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“…22,23 Normal expression of FLI-1 plays an important role in the production and evolution of megakaryocytes; in other words, it induces the expression of some genes involved in megakaryocyte maturation and differentiation, including GP6, c-mpl, GP9, and ITGA2B. 24,25 Although a heterozygous mutation has been recently discovered in FLI-1 leading to thrombocytopenia, 22 most disorders causing the impairment and defective function of FLI-1 are a function of a homozygous mutation or deletion in 11q chromosome. This heterozygous mutation is a missense mutation, which commonly occurs in codon970 of the gene and leads to the conversion of Arg to Trp in FLI-1 DNA-Binding domain.…”

Section: Oncogenes In Normal and Mutated Situation And Their Effect Omentioning

confidence: 99%

“…26 As a result, the transcriptional activity of FLI-1 target genes such as GP6, c-mpl, GP9, and ITGA2B decreases and subsequently leads to impaired production of platelets. 24 In general, mutation in FLI-1 causing impairment or loss of its function leads to Inherited Thrombocytopenia, especially Jacobson Syndrome and Paris-Trousseau Syndrome. As noted above, FLI-1 is located on 11q chromosome 23 and most patients with Paris Trousseau Syndrome lack FLI-1; 24 therefore, to achieve targeted therapy for differential diagnosis of this syndrome or to find the genetic defect of this disease, chromosome 11 (especially its long arm) can be assessed, or this molecule can be considered as a diagnostic factor of the disease.…”

Section: Oncogenes In Normal and Mutated Situation And Their Effect Omentioning

confidence: 99%

Prognostic significance of mutated genes in megakaryocytic disorders

et al. 2019

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Megakaryopoiesis is a process during which platelets that play a major role in hemostasis are produced due to differentiation and maturation of megakaryocytic precursors. Several genes, including oncogenes and tumor suppressor genes, play a role in the regulation of this process. This study was conducted to investigate the oncogenes and tumor suppressor genes as well as their mutations during the megakaryopoiesis process, which can lead to megakaryocytic disorders. Relevant literature was identified by a PubMed search (1998-2019) of English language papers using the terms ‘Megakaryopoiesis’, ‘Mutation’, ‘oncogenes’, and ‘Tumor Suppressor’. According to investigations, several mutations occur in the genes implicated in megakaryopoiesis, which abnormally induce or inhibit megakaryocyte production, differentiation, and maturation, leading to platelet disorders. GATA-1 is one of the important genes in megakaryopoiesis and its mutations can be considered among the factors involved in the incidence of these disorders. Considering the essential role of these genes (such as GATA- 1) in megakaryopoiesis and the involvement of their mutations in platelet disorders, study and examination of these changes can be a positive step in the diagnosis and prognosis of these diseases.

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Paris-Trousseau: evidence keeps pointing to FLI1

Cited by 4 publications

References 9 publications

Inherited platelet dysfunction and hematopoietic transcription factor mutations

Inherited platelet dysfunction and hematopoietic transcription factor mutations

Novel flavagline‐like compounds with potent Fli‐1 inhibitory activity suppress diverse types of leukemia

Prognostic significance of mutated genes in megakaryocytic disorders

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