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Reduced platelet formation associated with serine metabolic dysregulation in integrin αIIbβ3-deficient megakaryocytes.

Kato Ramaekers·My Tran·Marco Lunghi·Amy Hermans·Chantal Thys·Koenraad De Wispelaere·Ernest Turro·Chris Van Geet·Quentin Van Thillo·Kathelijne Peerlinck·Koji Eto·Alan T Nurden·Alessandra Balduini·Christian A Di Buduo·Veerle Labarque·Kathleen Freson
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Abstract

Glanzmann thrombasthenia (GT) is characterized by absent platelet aggregation in response to all agonists except ristocetin and is caused by recessive inactivating variants in ITGA2B or ITGB3. Although patients with GT typically are described as having normal platelet counts, autosomal dominant activating variants in ITGA2B or ITGB3 cause macrothrombocytopenia. Interestingly, in our cohort of 16 patients with GT, 8 consistently exhibited platelet counts at the lower end of the normal range. We studied the role of integrin αIIbβ3 in platelet formation using megakaryocytes (MKs) derived from genetically modified immortalized MK cell lines (imMKCLs), focusing on 2 modifications of ITGB3: ITGB3-/- (inactivating) and ITGB3WT/D673_E713del (activating). In static differentiation cultures, ITGB3-/- and ITGB3WT/D673_E713del imMKCLs exhibited normal MK differentiation but reduced proplatelet formation. Platelet production was also impaired in a 3-dimensional silk-based bone marrow system and in shaking cultures, confirming a quantitative role for ITGB3 in platelet production independent of the type of variant. Although thrombin receptor activating protein-activated, in vitro-generated platelets lacking αIIbβ3 failed to bind the activation-dependent PAC-1 antibody, ITGB3WT/D673_E713del platelets bound PAC-1 before activation, mimicking the patient's phenotype. Transcriptome profiling and metabolomic analyses of integrin αIIbβ3-deficient MKs revealed impaired serine metabolism and downregulation of SLC3A2 (CD98hc), an amino acid transporter chaperon known to interact with the β3 subunit. Flow cytometry confirmed decreased CD98hc in mutant MKs, whereas reexpression of wild-type ITGB3 in ITGB3-/- MKs restored αIIbβ3 and CD98hc expression, normalized proplatelet formation, and enhanced serine uptake. These results uncover a previously unrecognized role of integrin αIIbβ3 in coupling serine metabolism to platelet biogenesis.

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HumansMegakaryocytesBlood PlateletsThrombastheniaIntegrin beta3Platelet Glycoprotein GPIIb-IIIa ComplexSerineThrombopoiesisCell DifferentiationJournal Article

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Kato Ramaekers, My Tran, Marco Lunghi, Amy Hermans, Chantal Thys, Koenraad De Wispelaere, Ernest Turro, Chris Van Geet, Quentin Van Thillo, Kathelijne Peerlinck, Koji Eto, Alan T Nurden, Alessandra Balduini, Christian A Di Buduo, Veerle Labarque, Kathleen Freson. 2026-09-10. Reduced platelet formation associated with serine metabolic dysregulation in integrin αIIbβ3-deficient megakaryocytes.. https://doi.org/10.1182/blood.2025031904

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