Altered platelet-megakaryocyte endocytosis and trafficking of albumin and fibrinogen in RUNX1 haplodeficiency.
Autor: | Del Carpio-Cano F; Sol Sherry Thrombosis Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA., Mao G; Sol Sherry Thrombosis Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA., Goldfinger LE; Division of Hematology, Department of Medicine, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA., Wurtzel J; Division of Hematology, Department of Medicine, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA., Guan L; Sol Sherry Thrombosis Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA., Alam MA; Sol Sherry Thrombosis Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA., Lee K; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA.; Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies, Seoul, Korea., Poncz M; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA., Rao AK; Sol Sherry Thrombosis Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA.; Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA. |
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Jazyk: | angličtina |
Zdroj: | Blood advances [Blood Adv] 2024 Apr 09; Vol. 8 (7), pp. 1699-1714. |
DOI: | 10.1182/bloodadvances.2023011098 |
Abstrakt: | Abstract: Platelet α-granules have numerous proteins, some synthesized by megakaryocytes (MK) and others not synthesized but incorporated by endocytosis, an incompletely understood process in platelets/MK. Germ line RUNX1 haplodeficiency, referred to as familial platelet defect with predisposition to myeloid malignancies (FPDMMs), is associated with thrombocytopenia, platelet dysfunction, and granule deficiencies. In previous studies, we found that platelet albumin, fibrinogen, and immunoglobulin G (IgG) were decreased in a patient with FPDMM. We now show that platelet endocytosis of fluorescent-labeled albumin, fibrinogen, and IgG is decreased in the patient and his daughter with FPDMM. In megakaryocytic human erythroleukemia (HEL) cells, small interfering RNA RUNX1 knockdown (KD) increased uptake of these proteins over 24 hours compared with control cells, with increases in caveolin-1 and flotillin-1 (2 independent regulators of clathrin-independent endocytosis), LAMP2 (a lysosomal marker), RAB11 (a marker of recycling endosomes), and IFITM3. Caveolin-1 downregulation in RUNX1-deficient HEL cells abrogated the increased uptake of albumin, but not fibrinogen. Albumin, but not fibrinogen, partially colocalized with caveolin-1. RUNX1 KD resulted in increased colocalization of albumin with flotillin and fibrinogen with RAB11, suggesting altered trafficking of both proteins. The increased uptake of albumin and fibrinogen, as well as levels of caveolin-1, flotillin-1, LAMP2, and IFITM3, were recapitulated by short hairpin RNA RUNX1 KD in CD34+-derived MK. To our knowledge, these studies provide first evidence that platelet endocytosis of albumin and fibrinogen is impaired in some patients with RUNX1-haplodeficiency and suggest that megakaryocytes have enhanced endocytosis with defective trafficking, leading to loss of these proteins by distinct mechanisms. This study provides new insights into mechanisms governing endocytosis and α-granule deficiencies in RUNX1-haplodeficiency. (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.) |
Databáze: | MEDLINE |
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