15-deoxy-Δ12,14-PGJ2 enhances platelet production from megakaryocytes

O’Brien, Jamie J.; Spinelli, Sherry L.; Tober, Joanna; Blumberg, Neil; Francis, Charles W.; Taubman, Mark B.; Palis, James; Seweryniak, Kathryn E.; Gertz, Jacqueline M.; Phipps, Richard P.

doi:10.1182/blood-2008-05-158535

Cited by 92 publications

(70 citation statements)

References 49 publications

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“…In this regard, it has recently been shown that the inhibition of PP1a by ROS leads to the constitutive activation of the PI3K/ AKT pathway in leukaemic cells. 33 In addition, it has been shown that ROS are also important for platelet release, 34 this points to the importance of ROS not only in triggering differentiation programmes but also in terminal platelet release from mature megakaryocytes.…”

Section: Discussionmentioning

confidence: 99%

p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation

et al. 2010

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Transient reactive oxygen species (ROS) production is currently proving to be an important mechanism in the regulation of intracellular signalling, but reports showing the involvement of ROS in important biological processes, such as cell differentiation, are scarce. In this study, we show for the first time that ROS production is required for megakaryocytic differentiation in K562 and HEL cell lines and also in human CD34 þ cells. ROS production is transiently activated during megakaryocytic differentiation, and such production is abolished by the addition of different antioxidants (such as N-acetyl cysteine, trolox, quercetin) or the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor diphenylene iodonium. The inhibition of ROS formation hinders differentiation. RNA interference experiments have shown that a p22 phoxdependent NADPH oxidase activity is responsible for ROS production. In addition, the activation of ERK, AKT and JAK2 is required for differentiation, but the activation of phosphatidylinositol 3-kinase and c-Jun N-terminal kinase seems to be less important. When ROS production is prevented, the activation of these signalling pathways is partly inhibited. Taken together, these results show that NADPH oxidase ROS production is essential for complete activation of the main signalling pathways involved in megakaryocytopoiesis to occur. We suggest that this might also be important for in vivo megakaryocytopoiesis.

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Section: Discussionmentioning

confidence: 99%

p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation

et al. 2010

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“…The megakaryoblastic cell line MEG-01, established from the bone marrow of a patient with chronic myelogenous leukemia, 30,31 represents a useful model for the study of human megakaryopoiesis. MEG-01 cells treated with 2-AG underwent differentiation, characterized by loss of rounded morphology and gaining of a spinous phenotype with extended cytoplasmic protrusions, and by expression of surface markers specific for late stages of megakaryocyte maturation.…”

Section: Discussionmentioning

confidence: 99%

2-Arachidonoylglycerol enhances platelet formation from human megakaryoblasts

et al. 2014

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Platelets modulate vascular system integrity, and their loss is critical in haematological pathologies and after chemotherapy. Therefore, identification of molecules enhancing platelet production would be useful to counteract thrombocytopenia. We have previously shown that 2-arachidonoylglycerol (2-AG) acts as a true agonist of platelets, as well as it commits erythroid precursors toward the megakaryocytic lineage. Against this background, we sought to further interrogate the role of 2-AG in megakaryocyte/platelet physiology by investigating terminal differentiation, and subsequent thrombopoiesis. To this end, we used MEG-01 cells, a human megakaryoblastic cell line able to produce in vitro platelet-like particles.2-AG increased the number of cells showing ruffled surface and enhanced surface expression of specific megakaryocyte/platelet surface antigens, typical hallmarks of terminal megakaryocytic differentiation and platelet production. Changes in cytoskeleton modeling also occurred in differentiated megakaryocytes and blebbing platelets. 2-AG acted by binding to CB 1 and CB 2 receptors, because specific antagonists reverted its effect. Platelets were split off from megakaryocytes and were functional: they contained the platelet-specific surface markers CD61 and CD49, whose levels increased following stimulation with a natural agonist like collagen. Given the importance of 2-AG for driving megakaryopoiesis and thrombopoiesis, not surprisingly we found that its hydrolytic enzymes were tightly controlled by classical inducers of megakaryocyte differentiation.In conclusion 2-AG, by triggering megakaryocyte maturation and platelet release, may have clinical efficacy to counteract thrombocytopenia-related diseases.

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“…K-562 can be differentiated into various lineages depending of the inducer and MEG-01 can be differentiated toward the megakaryocytic pathway with several agents [18,19].…”

Section: Dac Treatment Induces Erythroid Differentiation Of K-562 Celmentioning

confidence: 99%

“…These results demonstrated that DAC induced only erythroid differentiation in K-562 based on the increase of GPA expression, the production of hemoglobin, and the absence of megakaryocytic markers. Finally, we completed this study by analyzing the particles derived from MEG-01, as this cell line is able to produce platelets similar in structure to freshly isolated human platelets [18]. DAC treatment of MEG-01 cells for 4 days caused an increase in platelets production ( Figure 3D, upper panel).…”

Section: Dac Treatment Induces Erythroid Differentiation Of K-562 Celmentioning

confidence: 99%

Sustained exposure to the DNA demethylating agent, 2′-deoxy-5-azacytidine, leads to apoptotic cell death in chronic myeloid leukemia by promoting differentiation, senescence, and autophagy

Schnekenburger

Grandjenette

Ghelfi

et al. 2011

Biochemical Pharmacology

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Sustained exposure to the DNA demethylating agent; 2'-deoxy-5-azacytidine; leads to apoptotic cell death in chronic myeloid leukemia by promoting differentiation; senescence; and autophagy. Biochemical Pharmacology, Elsevier, 2010, 81 (3) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Page 1 of 59A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 AbstractIn addition to its demethylating properties, 5-aza-2'-deoxycytidine (DAC) induces cell cycle arrest, differentiation, cell sensitization to chemotherapy, and cell death. However, the mechanisms by which DAC induces antiproliferation via these processes and how they are interconnected remain unclear. In this study, we found that a clinically relevant concentration of DAC triggered erythroid and megakaryocytic differentiation in the human chronic myeloid leukemia (CML) K-562 and MEG-01 cell lines, respectively. In addition, cells showed a marked increase in cell size in both cell lines and a more adhesive cell profile for MEG-01.Furthermore, DAC treatment induced cellular senescence and autophagy as shown by β-galactosidase staining and by autophagosome formation, respectively. After prolonged DAC treatment, phosphatidyl serine exposure, nuclear morphology analysis, and caspase cleavage revealed an activation of mitochondrial-dependent apoptosis in CML cells. This activation was accompanied by a decrease of anti-apoptotic proteins and an increase of calpain activity.Finally, we showed that combinatory treatment of relatively resistant CML with DAC and either conventional apoptotic inducers or with an histone deacetylase inhibitor increased synergistically apoptosis. We therefore conclude that induction of differentiation, senescence, and autophagy in CML are a key in cell sensitization and DAC-induced apoptosis.

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15-deoxy-Δ12,14-PGJ2 enhances platelet production from megakaryocytes

Cited by 92 publications

References 49 publications

p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation

p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation

2-Arachidonoylglycerol enhances platelet formation from human megakaryoblasts

Sustained exposure to the DNA demethylating agent, 2′-deoxy-5-azacytidine, leads to apoptotic cell death in chronic myeloid leukemia by promoting differentiation, senescence, and autophagy

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