Presence of a defect in karyokinesis during megakaryocyte endomitosis

Lordier, Larissa; Pan, Jiajia; Naim, Valeria; Jalil, Abdelali; Badirou, I.; Rameau, Philippe; Larghero, Jérôme; Debili, Najet; Rosselli, Filippo; Vainchenker, William; Chang, Yunhua

doi:10.4161/cc.22712

Cited by 23 publications

(21 citation statements)

References 18 publications

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“…[43][44][45][46][47] Cytological changes and modulation of surface receptor expression distinguish each step, making these features suitable markers for every stage of maturation. [48][49][50] In recent years, scientific progress has led to the production of functional platelets in vitro, in order to overcome problems related to platelet transfusion.…”

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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Section: Discussionmentioning

confidence: 99%

2-Arachidonoylglycerol enhances platelet formation from human megakaryoblasts

et al. 2014

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“…Ploidization is related to a process called endomitosis, which is a consequence of defective cytokinesis and karyokinesis [12–14]. The modal MK ploidy in the marrow is 16N and the ploidy level can reach 64N or more, indicating that the MK cell cycle is not blocked at 4N [15, 16].…”

Section: Introductionmentioning

confidence: 99%

P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis

et al. 2016

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TP53 also known as p53 is a tumor suppressor gene mutated in a variety of cancers. P53 is involved in cell cycle, apoptosis and DNA repair mechanisms and is thus tightly controlled by many regulators. Recently, strategies to treat cancer have focused on the development of MDM2 antagonists to induce p53 stabilization and restore cell death in p53 non-mutated cancers. However, some of these molecules display adverse effects in patients including induction of thrombocytopenia. In the present study, we have explored the effect of SAR405838 not only on human megakaryopoiesis but also more generally on hematopoiesis. We compared its effect to MI-219 and Nutlin, which are less potent MDM2 antagonists than SAR405838. We found that all these compounds induce a deleterious effect on all types of hematopoietic progenitors, as well as on erythroid and megakaryocytic differentiation. Moreover, they inhibit both early and late stages of megakaryopoiesis including ploidization and proplatelet formation. In conclusion, MDM2 antagonists induced a major hematopoietic defect in vitro as well as an inhibition of all stages of megakaryopoiesis that may account for in vivo thrombocytopenia observed in treated patients.

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“…This progression is characterized by a corresponding failure of karyokinesis and cytokinesis. 1,2 Although a direct correlation between polyploidy and platelet production has been observed, [3][4][5] significantly little is known regarding the regulation of endomitosis.…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of MCM7 and its intronic miRNA cluster miR-106b-25 during megakaryopoiesis induced polyploidy

Haldar

Roy

Banerjee³

2014

RNA Biology

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Megakaryocytes exit from mitotic cell cycle and enter a phase of repeated DNA replication without undergoing cell division, in a process termed as endomitosis of which little is known. We studied the expression of a DNA replication licensing factor mini chromosome maintenance protein 7 (MCM7) and its intronic miR-106b-25 cluster during mitotic and endo-mitotic cycles in megakaryocytic cell lines and in vitro cultured megakaryocytes obtained from human cord blood derived CD34C cells. Our results show that contrary to mitotic cell cycle, endomitosis proceeds with an uncoupling of the expression of MCM7 and miR-106b-25. This was attributed to the presence of a transcript variant of MCM7 which undergoes nonsense mediated decay (NMD). Additionally, miR-25 which was up regulated during endomitosis was found to promote megakaryopoiesis by inhibiting the expression of PTEN. Our study thus highlights the importance of a transcript variant of MCM7 destined for NMD in the modulation of megakaryopoiesis.

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Presence of a defect in karyokinesis during megakaryocyte endomitosis

Cited by 23 publications

References 18 publications

2-Arachidonoylglycerol enhances platelet formation from human megakaryoblasts

2-Arachidonoylglycerol enhances platelet formation from human megakaryoblasts

P53 activation inhibits all types of hematopoietic progenitors and all stages of megakaryopoiesis

Differential regulation of MCM7 and its intronic miRNA cluster miR-106b-25 during megakaryopoiesis induced polyploidy

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