FLI1 level during megakaryopoiesis affects thrombopoiesis and platelet biology
| العنوان: | FLI1 level during megakaryopoiesis affects thrombopoiesis and platelet biology |
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| المؤلفون: | Christopher S. Thom, Vincent Hayes, Danuta Jarocha, Mortimer Poncz, Deborah L. French, Karen K. Vo, Randolph B. Lyde, Spencer K. Sullivan |
| المصدر: | Blood. 129:3486-3494 |
| بيانات النشر: | American Society of Hematology, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Megakaryocyte differentiation, Cellular differentiation, Immunology, Biology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Megakaryocyte, medicine, Humans, Platelet, Jacobsen Distal 11q Deletion Syndrome, Thrombopoiesis, Megakaryopoiesis, Megakaryocytopoiesis, Proto-Oncogene Protein c-fli-1, Chromosomes, Human, Pair 11, fungi, Cell Biology, Hematology, Platelets and Thrombopoiesis, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, FLI1, Cancer research |
| الوصف: | Friend leukemia virus integration 1 (FLI1), a critical transcription factor (TF) during megakaryocyte differentiation, is among genes hemizygously deleted in Jacobsen syndrome, resulting in a macrothrombocytopenia termed Paris-Trousseau syndrome (PTSx). Recently, heterozygote human FLI1 mutations have been ascribed to cause thrombocytopenia. We studied induced-pluripotent stem cell (iPSC)-derived megakaryocytes (iMegs) to better understand these clinical disorders, beginning with iPSCs generated from a patient with PTSx and iPSCs from a control line with a targeted heterozygous FLI1 knockout (FLI1+/-). PTSx and FLI1+/- iMegs replicate many of the described megakaryocyte/platelet features, including a decrease in iMeg yield and fewer platelets released per iMeg. Platelets released in vivo from infusion of these iMegs had poor half-lives and functionality. We noted that the closely linked E26 transformation-specific proto-oncogene 1 (ETS1) is overexpressed in these FLI1-deficient iMegs, suggesting FLI1 negatively regulates ETS1 in megakaryopoiesis. Finally, we examined whether FLI1 overexpression would affect megakaryopoiesis and thrombopoiesis. We found increased yield of noninjured, in vitro iMeg yield and increased in vivo yield, half-life, and functionality of released platelets. These studies confirm FLI1 heterozygosity results in pleiotropic defects similar to those noted with other critical megakaryocyte-specific TFs; however, unlike those TFs, FLI1 overexpression improved yield and functionality. |
| تدمد: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2017-02-770958 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::52c5eb1b25d3e63c7a9371e1455d78ec https://doi.org/10.1182/blood-2017-02-770958 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....52c5eb1b25d3e63c7a9371e1455d78ec |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15280020 00064971 |
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| DOI: | 10.1182/blood-2017-02-770958 |