FLI1 monoallelic expression combined with its hemizygous loss underlies Paris-Trousseau/Jacobsen thrombopenia

Raslová, Hana; Komura, Emiko; Couedic, J P Le; Larbret, Frédéric; Debili, Najet; Feunteun, Jean; Danos, Olivier; Albagli, Olivier; Vainchenker, William; Favier, Rémi

doi:10.1172/jci200421197

Cited by 74 publications

(93 citation statements)

References 31 publications

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“…Friend leukaemia integration-1 (Fli-1), located on chromosome 11q24, is an Ets factor expressed in primary MKs and haemangioblasts. Its loss is associated with the Jacobsen/ Paris-Trousseau syndromes (Raslova et al, 2004) and thrombocytopenia with large fused granules within their abnormal blood platelets (Favier et al, 2003).…”

Section: Nuclear Transcription Factorsmentioning

confidence: 99%

Megakaryocyte development and platelet production

2006

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SummaryMegakaryocytopoiesis involves the commitment of haematopoietic stem cells, and the proliferation, maturation and terminal differentiation of the megakaryocytic progenitors. Circulating levels of thrombopoietin (TPO), the primary growth-factor for the megakaryocyte (MK) lineage, induce concentration-dependent proliferation and maturation of MK progenitors by binding to the c-Mpl receptor and signalling induction. Decreased platelet turnover rates results in increased concentration of free TPO, enabling the compensatory response of marrow MKs to increased platelet production. C-Mpl activity is orchestrated by a complex cascade of signalling molecules that induces the action of specific transcription factors to drive MK proliferation and maturation. Mature MKs form proplatelet projections that are fragmented into circulating particles. Newly developed thrombopoietic agents operating via c-Mpl receptor may prove useful in supporting platelet production in thrombocytopenic state. Herein, we review the regulation of megakaryocytopoiesis and platelet production in normal and disease state, and the new approaches to thrombopoietic therapy.

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Section: Nuclear Transcription Factorsmentioning

confidence: 99%

Megakaryocyte development and platelet production

2006

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“…Each RT product was divided into eight wells before performing nested PCR as described previously. 31 …”

Section: Single-cell Rt-pcr Analysismentioning

confidence: 99%

p210BCR-ABL reprograms transformed and normal human megakaryocytic progenitor cells into erythroid cells and suppresses FLI-1 transcription

et al. 2007

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The BCR-ABL oncoprotein exhibits deregulated protein tyrosine kinase activity and is implicated in the pathogenesis of Philadelphia chromosome (Ph)-positive human leukemias. Here, we report that ectopic expression of p210 BCR-ABL in the megakaryoblastic Mo7e cell line and in primary human CD34 þ progenitors trigger erythroid differentiation at the expense of megakaryocyte (MK) differentiation. Clonal culture of purified CD41 þ CD42 À cells, a population highly enriched in MK progenitors, combined with the conditional expression of p210 BCR-ABL tyrosine kinase activity by imatinib identified a true lineage reprogramming. In both Mo7e or CD41 þ CD42 À cells transduced with p210 BCR-ABL , lineage switching was associated with a downregulation of the friend leukemia Integration 1 (FLI-1) transcription factor. Re-expression of FLI-1 in p210 BCR-ABL -transduced Mo7e cells rescued the megakaryoblastic phenotype. Altogether, these results demonstrate that alteration of signal transduction via p210 BCR-ABL reprograms MK cells into erythroid cells by a downregulation of FLI-1. In addition, our findings underscore the role of kinases in lineage choice and infidelity in pathology and suggest that downregulation of FLI-1 may have important implications in CML pathogenesis. Leukemia (2007) 21, 917-925.

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“…Fli-1 is mutated in a number of cancers, including Ewing's sarcoma and erythroleukemia (2,3). Genetic manipulation in mice (4,5) and mutations in humans (4,6) have revealed multiple roles for Fli-1 in hematopoiesis including the production of megakaryocytes and platelets. Fli-1 is also implicated in the regulation of important stem cell genes, suggesting a role within the hematopoietic stem cell compartment (7,8).…”

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confidence: 99%

Dual requirement for the ETS transcription factors Fli-1 and Erg in hematopoietic stem cells and the megakaryocyte lineage

Kruse

Loughran

Baldwin³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Fli-1 and Erg are closely related members of the Ets family of transcription factors. Both genes are translocated in human cancers, including Ewing's sarcoma, leukemia, and in the case of Erg, more than half of all prostate cancers. Although evidence from mice and humans suggests that Fli-1 is required for megakaryopoiesis, and that Erg is required for normal adult hematopoietic stem cell (HSC) regulation, their precise physiological roles remain to be defined. To elucidate the relationship between Fli-1 and Erg in hematopoiesis, we conducted an analysis of mice carrying mutations in both genes. Our results demonstrate that there is a profound genetic interaction between Fli-1 and Erg. Double heterozygotes displayed phenotypes more dramatic than single heterozygotes: severe thrombocytopenia, with a significant deficit in megakaryocyte numbers and evidence of megakaryocyte dysmorphogenesis, and loss of HSCs accompanied by a reduction in the number of committed hematopoietic progenitor cells. These results illustrate an indispensable requirement for both Fli-1 and Erg in normal HSC and megakaryocyte homeostasis, and suggest these transcription factors may coregulate common target genes.T he E-twenty-six specific (Ets) proteins are a family of more than 20 helix-loop-helix domain transcription factors that have been implicated in a myriad of cellular processes (1). Fli-1 and Erg are Ets proteins that share greater homology to each other than to other Ets family members. Fli-1 is mutated in a number of cancers, including Ewing's sarcoma and erythroleukemia (2, 3). Genetic manipulation in mice (4, 5) and mutations in humans (4, 6) have revealed multiple roles for Fli-1 in hematopoiesis including the production of megakaryocytes and platelets. Fli-1 is also implicated in the regulation of important stem cell genes, suggesting a role within the hematopoietic stem cell compartment (7,8). Erg is also a proto-oncogene, translocated in Ewing sarcoma, leukemia, and prostate cancer (9-11). We recently reported a mouse model of Erg dysfunction, Erg Mld2 , in which an N-ethyl-N-nitrosourea (ENU)-induced point mutation causes profound loss of Erg function. These mice revealed an indispensable requirement for Erg in definitive hematopoiesis with Erg Mld2/Mld2 embryos dying at midgestation. Analyses of Erg ϩ/Mld2 adult mice revealed that Erg is required for normal adult HSC homeostasis. HSCs are reduced in number in Erg ϩ/Mld2 mice and unable to compete effectively with Erg ϩ/ϩ cells to reconstitute irradiated transplant recipients (12).In translocations driving Ewing's sarcoma, Fli-1 and Erg appear to be interchangeable; either Fli-1 or Erg can fuse with the gene encoding an RNA binding protein, EWS, and give rise to clinically indistinguishable disease (13). Moreover, in vitro data suggests that Fli-1 and Erg may heterodimerize to regulate sets of overlapping target genes (14, 15), raising the prospect that these proteins may, in part, be redundant. To explore the relationship between Fli-1 and Erg in a physiological setting, w...

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FLI1 monoallelic expression combined with its hemizygous loss underlies Paris-Trousseau/Jacobsen thrombopenia

Cited by 74 publications

References 31 publications

Megakaryocyte development and platelet production

Megakaryocyte development and platelet production

p210BCR-ABL reprograms transformed and normal human megakaryocytic progenitor cells into erythroid cells and suppresses FLI-1 transcription

Dual requirement for the ETS transcription factors Fli-1 and Erg in hematopoietic stem cells and the megakaryocyte lineage

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