Transcription factor RUNX1 regulates coagulation factor XIII-A (F13A1): decreased platelet-megakaryocyte F13A1 expression and clot contraction in RUNX1 haplodeficiency
Background: Germline RUNX1 haplodeficiency (RHD) is associated with thrombocytopenia, platelet dysfunction, and predisposition to myeloid malignancies. Platelet expression profiling of an RHD patient showed decreased F13A1, encoding for the A subunit of factor (F)XIII, a transglutaminase that cross-...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
|
| Series: | Research and Practice in Thrombosis and Haemostasis |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2475037925000044 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823861172106952704 |
|---|---|
| author | Fabiola Del Carpio-Cano Natthapol Songdej Liying Guan Guangfen Mao Lawrence E. Goldfinger Jeremy G.T. Wurtzel Kiwon Lee Michele P. Lambert Mortimer Poncz A. Koneti Rao |
| author_facet | Fabiola Del Carpio-Cano Natthapol Songdej Liying Guan Guangfen Mao Lawrence E. Goldfinger Jeremy G.T. Wurtzel Kiwon Lee Michele P. Lambert Mortimer Poncz A. Koneti Rao |
| author_sort | Fabiola Del Carpio-Cano |
| collection | DOAJ |
| description | Background: Germline RUNX1 haplodeficiency (RHD) is associated with thrombocytopenia, platelet dysfunction, and predisposition to myeloid malignancies. Platelet expression profiling of an RHD patient showed decreased F13A1, encoding for the A subunit of factor (F)XIII, a transglutaminase that cross-links fibrin and induces clot stabilization. FXIII-A is synthesized by hematopoietic cells, megakaryocytes, and monocytes. Objectives: To understand RUNX1 regulation of F13A1 expression in platelets/megakaryocytes and the mechanisms and consequences of decreased F13A1 in RHD. Methods: We performed studies in platelets, human erythroleukemia (HEL) cells, and human CD34+ cell-derived megakaryocytes including on clot contraction in cells following small inhibitor RNA knockdown (KD) of RUNX1 or F13A1. Results: Platelet F13A1 mRNA and protein were decreased in our index patient and in 2 siblings from an unrelated family with RHD. Platelet-driven clot contraction was decreased in the patient and affected daughter. Promoter studies in HEL cells showed that RUNX1 regulates F13A1 transcription; RUNX1 overexpression increased, and small inhibitor RNA RUNX1 KD reduced F13A1 promoter activity and protein. Following RUNX1 or F13A1 KD, clot contraction by HEL cells was decreased, as were FXIII-A surface expression, myosin light chain phosphorylation, and PAC1 antibody binding upon activation. F13A1 expression and clot contraction were impaired in RUNX1 downregulation in human megakaryocytes. Conclusion: RUNX1 regulates platelet-megakaryocyte F13A1 expression, which is decreased in RHD, reflecting regulation of a coagulation protein by a hematopoietic transcription factor. Platelet and megakaryocyte clot contraction is decreased in RHD, related to multiple impaired mechanisms including F13A1 expression, myosin phosphorylation, and αIIbβ3 activation. |
| format | Article |
| id | doaj-art-411df5e4bc834b42aad2f08d700ca0b5 |
| institution | Kabale University |
| issn | 2475-0379 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Research and Practice in Thrombosis and Haemostasis |
| spelling | doaj-art-411df5e4bc834b42aad2f08d700ca0b52025-02-10T04:34:43ZengElsevierResearch and Practice in Thrombosis and Haemostasis2475-03792025-01-0191102680Transcription factor RUNX1 regulates coagulation factor XIII-A (F13A1): decreased platelet-megakaryocyte F13A1 expression and clot contraction in RUNX1 haplodeficiencyFabiola Del Carpio-Cano0Natthapol Songdej1Liying Guan2Guangfen Mao3Lawrence E. Goldfinger4Jeremy G.T. Wurtzel5Kiwon Lee6Michele P. Lambert7Mortimer Poncz8A. Koneti Rao9Sol Sherry Thrombosis Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USASol Sherry Thrombosis Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA; Penn State College of Medicine/Penn State Cancer Institute, Hershey, Pennsylvania, USASol Sherry Thrombosis Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USASol Sherry Thrombosis Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USACardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania, USACardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, Pennsylvania, USADepartment of Pediatrics, Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies, Seoul, South KoreaDepartment of Pediatrics, Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USADepartment of Pediatrics, Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USASol Sherry Thrombosis Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA; Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA; Correspondence A. Koneti Rao, Sol Sherry Thrombosis Research Center and Section of Hematology, Lewis Katz School of Medicine at Temple University, 3420 N. Broad St., 204 MRB, Philadelphia, PA 19140, USA.Background: Germline RUNX1 haplodeficiency (RHD) is associated with thrombocytopenia, platelet dysfunction, and predisposition to myeloid malignancies. Platelet expression profiling of an RHD patient showed decreased F13A1, encoding for the A subunit of factor (F)XIII, a transglutaminase that cross-links fibrin and induces clot stabilization. FXIII-A is synthesized by hematopoietic cells, megakaryocytes, and monocytes. Objectives: To understand RUNX1 regulation of F13A1 expression in platelets/megakaryocytes and the mechanisms and consequences of decreased F13A1 in RHD. Methods: We performed studies in platelets, human erythroleukemia (HEL) cells, and human CD34+ cell-derived megakaryocytes including on clot contraction in cells following small inhibitor RNA knockdown (KD) of RUNX1 or F13A1. Results: Platelet F13A1 mRNA and protein were decreased in our index patient and in 2 siblings from an unrelated family with RHD. Platelet-driven clot contraction was decreased in the patient and affected daughter. Promoter studies in HEL cells showed that RUNX1 regulates F13A1 transcription; RUNX1 overexpression increased, and small inhibitor RNA RUNX1 KD reduced F13A1 promoter activity and protein. Following RUNX1 or F13A1 KD, clot contraction by HEL cells was decreased, as were FXIII-A surface expression, myosin light chain phosphorylation, and PAC1 antibody binding upon activation. F13A1 expression and clot contraction were impaired in RUNX1 downregulation in human megakaryocytes. Conclusion: RUNX1 regulates platelet-megakaryocyte F13A1 expression, which is decreased in RHD, reflecting regulation of a coagulation protein by a hematopoietic transcription factor. Platelet and megakaryocyte clot contraction is decreased in RHD, related to multiple impaired mechanisms including F13A1 expression, myosin phosphorylation, and αIIbβ3 activation.http://www.sciencedirect.com/science/article/pii/S2475037925000044clotF13A1FXIIImegakaryocytesplateletsRUNX1 |
| spellingShingle | Fabiola Del Carpio-Cano Natthapol Songdej Liying Guan Guangfen Mao Lawrence E. Goldfinger Jeremy G.T. Wurtzel Kiwon Lee Michele P. Lambert Mortimer Poncz A. Koneti Rao Transcription factor RUNX1 regulates coagulation factor XIII-A (F13A1): decreased platelet-megakaryocyte F13A1 expression and clot contraction in RUNX1 haplodeficiency Research and Practice in Thrombosis and Haemostasis clot F13A1 FXIII megakaryocytes platelets RUNX1 |
| title | Transcription factor RUNX1 regulates coagulation factor XIII-A (F13A1): decreased platelet-megakaryocyte F13A1 expression and clot contraction in RUNX1 haplodeficiency |
| title_full | Transcription factor RUNX1 regulates coagulation factor XIII-A (F13A1): decreased platelet-megakaryocyte F13A1 expression and clot contraction in RUNX1 haplodeficiency |
| title_fullStr | Transcription factor RUNX1 regulates coagulation factor XIII-A (F13A1): decreased platelet-megakaryocyte F13A1 expression and clot contraction in RUNX1 haplodeficiency |
| title_full_unstemmed | Transcription factor RUNX1 regulates coagulation factor XIII-A (F13A1): decreased platelet-megakaryocyte F13A1 expression and clot contraction in RUNX1 haplodeficiency |
| title_short | Transcription factor RUNX1 regulates coagulation factor XIII-A (F13A1): decreased platelet-megakaryocyte F13A1 expression and clot contraction in RUNX1 haplodeficiency |
| title_sort | transcription factor runx1 regulates coagulation factor xiii a f13a1 decreased platelet megakaryocyte f13a1 expression and clot contraction in runx1 haplodeficiency |
| topic | clot F13A1 FXIII megakaryocytes platelets RUNX1 |
| url | http://www.sciencedirect.com/science/article/pii/S2475037925000044 |
| work_keys_str_mv | AT fabioladelcarpiocano transcriptionfactorrunx1regulatescoagulationfactorxiiiaf13a1decreasedplateletmegakaryocytef13a1expressionandclotcontractioninrunx1haplodeficiency AT natthapolsongdej transcriptionfactorrunx1regulatescoagulationfactorxiiiaf13a1decreasedplateletmegakaryocytef13a1expressionandclotcontractioninrunx1haplodeficiency AT liyingguan transcriptionfactorrunx1regulatescoagulationfactorxiiiaf13a1decreasedplateletmegakaryocytef13a1expressionandclotcontractioninrunx1haplodeficiency AT guangfenmao transcriptionfactorrunx1regulatescoagulationfactorxiiiaf13a1decreasedplateletmegakaryocytef13a1expressionandclotcontractioninrunx1haplodeficiency AT lawrenceegoldfinger transcriptionfactorrunx1regulatescoagulationfactorxiiiaf13a1decreasedplateletmegakaryocytef13a1expressionandclotcontractioninrunx1haplodeficiency AT jeremygtwurtzel transcriptionfactorrunx1regulatescoagulationfactorxiiiaf13a1decreasedplateletmegakaryocytef13a1expressionandclotcontractioninrunx1haplodeficiency AT kiwonlee transcriptionfactorrunx1regulatescoagulationfactorxiiiaf13a1decreasedplateletmegakaryocytef13a1expressionandclotcontractioninrunx1haplodeficiency AT micheleplambert transcriptionfactorrunx1regulatescoagulationfactorxiiiaf13a1decreasedplateletmegakaryocytef13a1expressionandclotcontractioninrunx1haplodeficiency AT mortimerponcz transcriptionfactorrunx1regulatescoagulationfactorxiiiaf13a1decreasedplateletmegakaryocytef13a1expressionandclotcontractioninrunx1haplodeficiency AT akonetirao transcriptionfactorrunx1regulatescoagulationfactorxiiiaf13a1decreasedplateletmegakaryocytef13a1expressionandclotcontractioninrunx1haplodeficiency |