{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T10:29:00Z","timestamp":1794047340116,"version":"4.8.0"},"reference-count":50,"publisher":"Ferrata Storti Foundation (Haematologica)","issue":"10","license":[{"start":{"date-parts":[[2019,11,21]],"date-time":"2019-11-21T00:00:00Z","timestamp":1574294400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["haematol"],"abstract":"<jats:p>GFI1B-related thrombocytopenia (GFI1B-RT) is a rare bleeding disorder mainly caused by the presence of truncated GFI1B proteins with dominant-negative properties. The disease is characterized by low platelet counts, the presence of abnormal platelets, a megakaryocytic expansion and mild erythroid defects. However, no animal models faithfully reproducing the GFI1B-RT phenotype observed in patients exist. We had previously generated mice with floxed Gfi1b alleles that can be eliminated by Cre recombinase, but those animals developed a much more severe phenotype than GFI1B-RT patients and were of limited interest in assessing the disease. Using CRISPR\/Cas9 technology, we have now established three independent mouse lines that carry mutated Gfi1b alleles producing proteins lacking DNA binding zinc fingers and thereby acting in a dominant negative (DN) manner. Mice heterozygous for these Gfi1b-DN alleles show reduced platelet counts and an expansion of megakaryocytes similar to features of human GFI1B-RT but lacking the distinctively large agranular platelets. In addition, Gfi1b-DN mice exhibit an expansion of erythroid precursors indicative of a mildly abnormal erythropoiesis but without noticeable red blood cell defects. When associated with megakaryocyte-specific ablation of the remaining allele, the Gfi1b-DN alleles triggered erythroid-specific deleterious defects. Gfi1b-DN mice also showed a delayed recovery from platelet depletion, indicating a defect in stress thrombopoiesis. However, injecting Gfi1b-DN mice with romiplostim, a thrombopoietin receptor super agonist, increased platelet numbers even beyond normal levels. Thus, our data support a causal link between DN mutations in GFI1B and thrombocytopenia and suggest that patients with GFI1B-RT could be treated successfully with thrombopoietin agonists.<\/jats:p>","DOI":"10.3324\/haematol.2019.222596","type":"journal-article","created":{"date-parts":[[2019,11,21]],"date-time":"2019-11-21T15:25:21Z","timestamp":1574349921000},"page":"2457-2470","source":"Crossref","is-referenced-by-count":10,"title":["Dominant negative Gfi1b mutations cause moderate thrombocytopenia and an impaired stress thrombopoiesis associated with mild erythropoietic abnormalities in mice"],"prefix":"10.3324","volume":"105","author":[{"family":"Hugues Beauchemin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Peiman Shooshtharizadeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Jordan Pinder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Graham Dellaire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Tarik M\u00f6r\u00f6y","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1856","published-online":{"date-parts":[[2019,11,21]]},"reference":[{"key":"13111","doi-asserted-by":"crossref","unstructured":"Tong B, Grimes HL, Yang TY. 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