Document Type
Article
Publication Date
1-16-2025
Abstract
BACKGROUND: Germline RUNX1 haplodeficiency (RHD) is associated with thrombocy- topenia, 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: o understand RUNX1 regulation of F13A1 expression in platelets/mega- karyocytes 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 phos- phorylation, and αIIbβ3 activation.
Recommended Citation
Del Carpio-Cano, Fabiola; Songdej, Natthapol; Guan, Liying; Mao, Guangfen; Goldfinger, Lawrence E.; Wurtzel, Jeremy G.T.; Lee, Kiwon; Lambert, Michele P.; Poncz, Mortimer; and Rao, A. Koneti, "Transcription Factor RUNX1 Regulates Coagulation Factor XIII-A (F13A1): Decreased Platelet-Megakaryocyte F13A1 Expression and Clot Contraction in RUNX1 Haplodeficiency" (2025). Cardeza Foundation for Hematologic Research. Paper 85.
https://jdc.jefferson.edu/cardeza_foundation/85
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Language
English
Included in
Amino Acids, Peptides, and Proteins Commons, Hematology Commons, Hemic and Immune Systems Commons
Comments
This article is the author's final published version in Research and Practice in Thrombosis and Haemostasis, Volume 9, Issue 1, January 2025, Article number 102680.
The published version is available at https://doi.org/10.1016/j.rpth.2025.102680.
Copyright © 2025 The Authors