Journal of thrombosis and haemostasis : JTH · 2025
Growth factor independent 1B is a metabolic regulator that exerts pleiotropic effects on platelet function.
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Morel-Kopp Marie-Christine, Levade Marie, Beutler Lucinda, Chen Qiang, Othman Jad, Steffen Pascal, McKay Matthew J, Molloy Mark P, Selvadurai Maria V, Liang Helena P H, Whittaker Shane, van der Wal Dianne E, Gabrielli Sara, Hamilton Justin R, Chen Vivien M, Ng Ashley P, Ward Christopher M, Stevenson William S
Аннотация
BACKGROUND: Human variants in the growth factor independent 1B (GFI1B) transcription factor are associated with thrombocytopenia and a variable bleeding phenotype.
OBJECTIVES: In this study, we examined the bleeding phenotype associated with the human GFI1BH294fs variant and compared it with a mouse model of abnormal GFI1B function.
METHODS: The transcriptomic and proteomic profiles of human GFI1BH294fs platelets were analyzed and compared with those of murine megakaryocytes harboring conditional deletion of Gfi1b. Observed changes were subsequently validated with imaging and western blotting and in a cell model of endocytosis.
RESULTS: All individuals with the GFI1BH294fs variant displayed markedly impaired or absent platelet aggregation responses to collagen stimulation as assessed by light transmission aggregometry. Mice with conditional deletion of Gfi1b in the megakaryocyte lineage had severe thrombocytopenia with increased numbers of abnormal megakaryocytes and progenitors. Proteomic pathway analysis of human platelets and mouse megakaryocytes revealed defects in platelet aggregation and spreading, dysregulated glycoprotein VI and integrin signaling, and reduced endocytosis. Megakaryocytes deficient in Gfi1b displayed structural abnormalities and endocytosis failure with decreased fibrinogen uptake from surrounding media consistent with the fibrinogen deficiency observed in human GFI1BH294fs platelets. Unexpectedly, oxidative phosphorylation was upregulated in both platelets and megakaryocytes, and this was associated with mitochondrial hyperplasia on cell imaging. Pyruvate kinase M2 emerged as a potential mediator of these metabolic changes.
CONCLUSION: Dysregulated GFI1B function affects multiple biological pathways linked to abnormal bleeding. Reduced GFI1B activity also induces metabolic reprogramming in platelets and megakaryocytes, leading to enhanced oxidative phosphorylation.
OBJECTIVES: In this study, we examined the bleeding phenotype associated with the human GFI1BH294fs variant and compared it with a mouse model of abnormal GFI1B function.
METHODS: The transcriptomic and proteomic profiles of human GFI1BH294fs platelets were analyzed and compared with those of murine megakaryocytes harboring conditional deletion of Gfi1b. Observed changes were subsequently validated with imaging and western blotting and in a cell model of endocytosis.
RESULTS: All individuals with the GFI1BH294fs variant displayed markedly impaired or absent platelet aggregation responses to collagen stimulation as assessed by light transmission aggregometry. Mice with conditional deletion of Gfi1b in the megakaryocyte lineage had severe thrombocytopenia with increased numbers of abnormal megakaryocytes and progenitors. Proteomic pathway analysis of human platelets and mouse megakaryocytes revealed defects in platelet aggregation and spreading, dysregulated glycoprotein VI and integrin signaling, and reduced endocytosis. Megakaryocytes deficient in Gfi1b displayed structural abnormalities and endocytosis failure with decreased fibrinogen uptake from surrounding media consistent with the fibrinogen deficiency observed in human GFI1BH294fs platelets. Unexpectedly, oxidative phosphorylation was upregulated in both platelets and megakaryocytes, and this was associated with mitochondrial hyperplasia on cell imaging. Pyruvate kinase M2 emerged as a potential mediator of these metabolic changes.
CONCLUSION: Dysregulated GFI1B function affects multiple biological pathways linked to abnormal bleeding. Reduced GFI1B activity also induces metabolic reprogramming in platelets and megakaryocytes, leading to enhanced oxidative phosphorylation.