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• W2767020540 abstract "•MK endomitosis is associated with both a defect in cytokinesis and karyokinesis.•A myosin II accumulation defect at the furrow induces the cytokinesis failure.•MK polyploidization and maturation have close transcriptional regulation.•MK ploidization is functionally important for efficient platelet production.•MK ploidy is altered in many pathologies but associated with maturation defects. In mammals, platelets are produced in the blood by cytoplasmic fragmentation of megakaryocytes (MKs). Platelet production is thus dependent on both the MK number and size. During differentiation, MKs switch from a division by mitosis to polyploidization by endomitosis to increase their size. The endomitotic process includes several successive rounds of DNA replication with an entry in mitosis with a failure in late cytokinesis and a defect in karyokinesis. This leads to a giant cell with a modal ploidy at 16N and one multilobulated nucleus. The entire genome is duplicated several times and all alleles remain functional producing a hypermetabolic cell. A defect in abscission explains the cytokinesis failure and is related to an altered accumulation of actomyosin at the cleavage furrow as a consequence of both a low local RhoA activity and silencing of the MYH10 gene. This mechanism is regulated by transcription factors that govern differentiation explaining the intricacies of both processes. However, the endomitotic cell cycle regulation is still incompletely understood, particularly mitosis entry, escape to the tetraploid checkpoint, and defect in karyokinesis. Polyploidization is regulated during ontogeny, the first embryonic MKs being 2N. The molecular mechanism of this embryo–fetal/adult transition is beginning to be understood. In physiological conditions, MK ploidy is increased by an enhanced platelet demand through the thrombopoietin/myeloproliferative leukemia axis. In numerous hematologic malignancies, MK ploidy decreases, but it is always associated with a defect in MK differentiation. It has been proposed that polyploidization induction could be a treatment for some malignant MK disorders. In mammals, platelets are produced in the blood by cytoplasmic fragmentation of megakaryocytes (MKs). Platelet production is thus dependent on both the MK number and size. During differentiation, MKs switch from a division by mitosis to polyploidization by endomitosis to increase their size. The endomitotic process includes several successive rounds of DNA replication with an entry in mitosis with a failure in late cytokinesis and a defect in karyokinesis. This leads to a giant cell with a modal ploidy at 16N and one multilobulated nucleus. The entire genome is duplicated several times and all alleles remain functional producing a hypermetabolic cell. A defect in abscission explains the cytokinesis failure and is related to an altered accumulation of actomyosin at the cleavage furrow as a consequence of both a low local RhoA activity and silencing of the MYH10 gene. This mechanism is regulated by transcription factors that govern differentiation explaining the intricacies of both processes. However, the endomitotic cell cycle regulation is still incompletely understood, particularly mitosis entry, escape to the tetraploid checkpoint, and defect in karyokinesis. Polyploidization is regulated during ontogeny, the first embryonic MKs being 2N. The molecular mechanism of this embryo–fetal/adult transition is beginning to be understood. In physiological conditions, MK ploidy is increased by an enhanced platelet demand through the thrombopoietin/myeloproliferative leukemia axis. In numerous hematologic malignancies, MK ploidy decreases, but it is always associated with a defect in MK differentiation. It has been proposed that polyploidization induction could be a treatment for some malignant MK disorders. Megakaryopoiesis is the differentiation process leading to platelet production and one of the most original cellular systems in mammals: platelets derive from the fragmentation of megakaryocytes (MKs) and the regulation of platelet production is dependent on the global MK cytoplasmic mass, which relies on the MK number and size. To increase the cytoplasmic mass of each MK, mammalian megakaryopoiesis in late differentiation has switched from a classical mitosis to polyploidization leading to the production a giant cell [1Bluteau D. Lordier L. Di Stefano A. et al.Regulation of megakaryocyte maturation and platelet formation.J Thromb Haemost. 2009; 7: 227-234Crossref PubMed Scopus (0) Google Scholar, 2Ravid K. Lu J. Zimmet J.M. Jones M.R. Roads to polyploidy: the megakaryocyte example.J Cell Physiol. 2002; 190: 7-20Crossref PubMed Scopus (180) Google Scholar, 3Zimmet J. Ravid K. Polyploidy: occurrence in nature, mechanisms, and significance for the megakaryocyte-platelet system.Exp Hematol. 2000; 28: 3-16Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Here, we review the mechanisms behind the endomitotic process and its regulation in normal and pathological megakaryopoiesis. Megakaryopoiesis derives from the differentiation of a multipotent hematopoietic stem cell (HSC) with self-renewal capacities. This HSC commits toward different cell types, including the MK fate, by providing a MK-committed progenitor. The main early characteristic of the MK lineage is the existence of MK/platelet-biased HSC capable of giving rise to MKs and platelets in a few steps in case of emergency [4Sanjuan-Pla A. Macaulay I.C. Jensen C.T. et al.Platelet-biased stem cells reside at the apex of the haematopoietic stem-cell hierarchy.Nature. 2013; 502: 232-236Crossref PubMed Scopus (139) Google Scholar] and the existence of a bipotent erythroid/MK progenitor (MK-P) [5Notta F. Zandi S. Takayama N. et al.Distinct routes of lineage development reshape the human blood hierarchy across ontogeny.Science. 2016; 351: aab2116Crossref PubMed Scopus (108) Google Scholar]. The MK progenitors are heterogeneous and include the MK-Ps, which express CD41 [6Miyawaki K. Iwasaki H. Jiromaru T. et al.Identification of unipotent megakaryocyte progenitors in human hematopoiesis.Blood. 2017; 129: 3332-3343Crossref PubMed Scopus (19) Google Scholar]. These progenitors differentiate through cell divisions to generate cells expressing the main platelet proteins such as CD41 and CD42, which are associated with early differentiation markers. These 2N cells, also called promegakaryoblasts, will switch from a mitotic to an endomitotic process to give rise to polyploid megakaryoblasts and MKs [1Bluteau D. Lordier L. Di Stefano A. et al.Regulation of megakaryocyte maturation and platelet formation.J Thromb Haemost. 2009; 7: 227-234Crossref PubMed Scopus (0) Google Scholar]. When polyploidization arrests, MKs largely increase their cytoplasmic mass by increasing protein synthesis and developing organelles such as the demarcation membrane system (DMS) and specific granules. They also reorganize their cytoskeleton to ultimately form long pseudopods called proplatelets [7Machlus K.R. Italiano Jr, J.E. The incredible journey: from megakaryocyte development to platelet formation.J Cell Biol. 2013; 201: 785-796Crossref PubMed Scopus (149) Google Scholar] (Fig. 1). MK differentiation takes place essentially in the bone marrow (BM) in the human adult. However, the final generation of platelets is localized in blood, in the marrow sinusoids, by the rupture of proplatelets that have extended from the MKs through the endothelial barrier. MKs can also entirely migrate in blood and produce platelets in the pulmonary circulation [7Machlus K.R. Italiano Jr, J.E. The incredible journey: from megakaryocyte development to platelet formation.J Cell Biol. 2013; 201: 785-796Crossref PubMed Scopus (149) Google Scholar, 8Tavassoli M. Aoki M. Migration of entire megakaryocytes through the marrow–blood barrier.Br J Haematol. 1981; 48: 25-29Crossref PubMed Google Scholar, 9Junt T. Schulze H. Chen Z. et al.Dynamic visualization of thrombopoiesis within bone marrow.Science. 2007; 317: 1767-1770Crossref PubMed Scopus (331) Google Scholar, 10Lefrancais E. Ortiz-Munoz G. Caudrillier A. et al.The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors.Nature. 2017; 544: 105-109Crossref PubMed Scopus (40) Google Scholar, 11Slater D.N. Trowbridge E.A. Martin J.F. The megakaryocyte in thrombocytopenia: a microscopic study which supports the theory that platelets are produced in the pulmonary circulation.Thromb Res. 1983; 31: 163-176Abstract Full Text PDF PubMed Google Scholar]. It has also been suggested that a part of MK differentiation may take place in the lungs [10Lefrancais E. Ortiz-Munoz G. Caudrillier A. et al.The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors.Nature. 2017; 544: 105-109Crossref PubMed Scopus (40) Google Scholar, 12Sharma G.K. Talbot I.C. Pulmonary megakaryocytes: “missing link” between cardiovascular and respiratory disease?.J Clin Pathol. 1986; 39: 969-976Crossref PubMed Google Scholar]. Extracellular regulation of polyploidization, but not proplatelet formation, is dependent on thrombopoietin (TPO), a hormonal factor that binds to its cognate receptor, MPL/TPOR, to activate a downstream signaling cascade entirely dependent on Janus kinase 2 (JAK2) [13Kaushansky K. Thrombopoietin and its receptor in normal and neoplastic hematopoiesis.Thromb J. 2016; 14: 40Crossref PubMed Scopus (0) Google Scholar]. Cell-autonomous processes are dominated by transcriptional regulation based on large transcription factor (TF) complexes [14Tijssen M.R. Cvejic A. Joshi A. et al.Genome-wide analysis of simultaneous GATA1/2, RUNX1, FLI1, and SCL binding in megakaryocytes identifies hematopoietic regulators.Dev Cell. 2011; 20: 597-609Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 15Tijssen M.R. Ghevaert C. Transcription factors in late megakaryopoiesis and related platelet disorders.J Thromb Haemost. 2013; 11: 593-604Crossref PubMed Scopus (27) Google Scholar]. MKs have a ploidy of a 2XN ranging from 2N to 64N with a modal ploidy of 16N [2Ravid K. Lu J. Zimmet J.M. Jones M.R. Roads to polyploidy: the megakaryocyte example.J Cell Physiol. 2002; 190: 7-20Crossref PubMed Scopus (180) Google Scholar]. In certain stress conditions, the ploidy level can be even higher. Polyploidization is dispensable for terminal MK maturation and some 2N and 4N MKs called micro-MKs can be fully mature, giving rise to platelets [16Vainchenker W. Guichard J. Breton-Gorius J. [Differentiation of human megakaryocytes in culture starting from the primordial circulating cells in the newborn].C R Acad Sci Hebd Seances Acad Sci D. 1978; 287: 177-179PubMed Google Scholar]. These are more frequent in fetal liver and in culture of cord blood cells, as well as in pathologies [17Liu Z.J. Italiano Jr, J. Ferrer-Marin F. et al.Developmental differences in megakaryocytopoiesis are associated with up-regulated TPO signaling through mTOR and elevated GATA-1 levels in neonatal megakaryocytes.Blood. 2011; 117: 4106-4117Crossref PubMed Scopus (48) Google Scholar, 18Hegyi E. Navarro S. Debili N. et al.Regulation of human megakaryocytopoiesis: analysis of proliferation, ploidy and maturation in liquid cultures.Int J Cell Cloning. 1990; 8: 236-244Crossref PubMed Google Scholar]. MK polyploidy involves several successive rounds of DNA replication that could be achieved by two different mechanisms: endoreplication with endocycles, the most common mechanism in Drosophila, plants, and trophoblasts, or by endomitosis [2Ravid K. Lu J. Zimmet J.M. Jones M.R. Roads to polyploidy: the megakaryocyte example.J Cell Physiol. 2002; 190: 7-20Crossref PubMed Scopus (180) Google Scholar, 3Zimmet J. Ravid K. Polyploidy: occurrence in nature, mechanisms, and significance for the megakaryocyte-platelet system.Exp Hematol. 2000; 28: 3-16Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 19Trakala M. Rodriguez-Acebes S. Maroto M. et al.Functional reprogramming of polyploidization in megakaryocytes.Dev Cell. 2015; 32: 155-167Abstract Full Text Full Text PDF PubMed Google Scholar]; these two processes differ by the absence or presence of a mitosis entry, respectively. Preliminary morphological studies confirmed the presence of a mitotic entry in polyploid MKs. Later, by studying TPO-induced MK differentiation from MK progenitors in vitro, the MK endomitosis process was described in detail [20Nagata Y. Muro Y. Todokoro K. Thrombopoietin-induced polyploidization of bone marrow megakaryocytes is due to a unique regulatory mechanism in late mitosis.J Cell Biol. 1997; 139: 449-457Crossref PubMed Scopus (0) Google Scholar, 21Vitrat N. Cohen-Solal K. Pique C. et al.Endomitosis of human megakaryocytes are due to abortive mitosis.Blood. 1998; 91: 3711-3723PubMed Google Scholar]. During polyploidization, MKs enter into mitosis, developing a complex multipolar spindle (2N poles between 2N and 4N, four poles between 4N and 8N, etc.), with an asymmetrical segregation of the chromosomes toward the different poles, but without functional consequence because only one multilobulated nucleus is formed [22Roy L. Coullin P. Vitrat N. et al.Asymmetrical segregation of chromosomes with a normal metaphase/anaphase checkpoint in polyploid megakaryocytes.Blood. 2001; 97: 2238-2247Crossref PubMed Scopus (0) Google Scholar] (Figure 2, Figure 3). In early studies, the different stages of mitosis until anaphase were observed, suggesting that endomitosis was an abortive mitosis, skipping telophase and cytokinesis [20Nagata Y. Muro Y. Todokoro K. Thrombopoietin-induced polyploidization of bone marrow megakaryocytes is due to a unique regulatory mechanism in late mitosis.J Cell Biol. 1997; 139: 449-457Crossref PubMed Scopus (0) Google Scholar, 21Vitrat N. Cohen-Solal K. Pique C. et al.Endomitosis of human megakaryocytes are due to abortive mitosis.Blood. 1998; 91: 3711-3723PubMed Google Scholar] (Fig. 2). Further experiments mostly based on time-lapse microscopy have shown definitively that endomitosis is a defect in late cytokinesis [23Geddis A.E. Fox N.E. Tkachenko E. Kaushansky K. Endomitotic megakaryocytes that form a bipolar spindle exhibit cleavage furrow ingression followed by furrow regression.Cell Cycle. 2007; 6: 455-460Crossref PubMed Google Scholar, 24Lordier L. Jalil A. Aurade F. et al.Megakaryocyte endomitosis is a failure of late cytokinesis related to defects in the contractile ring and Rho/Rock signaling.Blood. 2008; 112: 3164-3174Crossref PubMed Scopus (107) Google Scholar] (Fig. 3). In the transition from 2N to 4N, there is a true telophase and the two daughter cells are nearly separated with an apparently normal midzone and the formation of a cleavage furrow. However, in endomitotic MKs, there is a rapid regression of the furrow and the two daughter cells fuse together. A similar phenomenon occurs during the 4N to 8N transition and to higher ploidy with a morphology with a “rose petal” appearance (Fig. 3). However, the abnormalities in furrow ingression are more important, with minimal cell elongation and chromosome segregation [26Papadantonakis N. Makitalo M. McCrann D.J. et al.Direct visualization of the endomitotic cell cycle in living megakaryocytes: differential patterns in low and high ploidy cells.Cell Cycle. 2008; 7: 2352-2356Crossref PubMed Google Scholar]. Usually, a pure defect in cytokinesis gives rise to a multinucleated cell, but in MKs, there is also a karyokinesis abnormality with the persistence of nucleoplasmic bridges between the two nuclei at the 2N to 4N transition [27Lordier L. Pan J. Naim V. et al.Presence of a defect in karyokinesis during megakaryocyte endomitosis.Cell Cycle. 2012; 11: 4385-4389Crossref PubMed Scopus (11) Google Scholar]. Thereafter, the two nuclei are incompletely separated and, when the daughter cells fuse together, they merge their nuclei to give a 4N cell with a single bilobulated nucleus [27Lordier L. Pan J. Naim V. et al.Presence of a defect in karyokinesis during megakaryocyte endomitosis.Cell Cycle. 2012; 11: 4385-4389Crossref PubMed Scopus (11) Google Scholar]. This transition from mitosis to endomitosis does not seem to be irreversible because some 4N MKs may divide again with a true cytokinesis [28Leysi-Derilou Y. Robert A. Duchesne C. Garnier A. Boyer L. Pineault N. Polyploid megakaryocytes can complete cytokinesis.Cell Cycle. 2010; 9: 2589-2599Crossref PubMed Scopus (0) Google Scholar]. A schematic illustration of the endomitotic process is shown in Fig. 4.Figure 4Schematic comparison of mitosis with MK endomitosis.View Large Image Figure ViewerDownload Hi-res image Download (PPT) MKs and post-endomitotic MKs express high levels of cyclins D1 and D3 [29Wang Z. Zhang Y. Kamen D. Lees E. Ravid K. Cyclin D3 is essential for megakaryocytopoiesis.Blood. 1995; 86: 3783-3788PubMed Google Scholar]. Their overexpression increases the number and the ploidy of BM MKs, but not platelet production, due to abnormalities in the DMS [30Sun S. Zimmet J.M. Toselli P. Thompson A. Jackson C.W. Ravid K. Overexpression of cyclin D1 moderately increases ploidy in megakaryocytes.Haematologica. 2001; 86: 17-23PubMed Google Scholar]. In contrast to dividing cells, cyclin E is indispensable for endomitosis and endocycle [31Geng Y. Yu Q. Sicinska E. et al.Cyclin E ablation in the mouse.Cell. 2003; 114: 431-443Abstract Full Text Full Text PDF PubMed Scopus (500) Google Scholar] because its overexpression increases MK ploidy with a modal ploidy at 32N [32Eliades A. Papadantonakis N. Ravid K. New roles for cyclin E in megakaryocytic polyploidization.J Biol Chem. 2010; 285: 18909-18917Crossref PubMed Scopus (0) Google Scholar]. Cyclin E acts by regulating the pre-replication complex, particularly the minichromosomal maintenance factor (Mcm) and Cdc6. Overexpression of Cdc6 in MK cell lines also induces an increase in ploidy [33Bermejo R. Vilaboa N. Cales C. Regulation of CDC6, geminin, and CDT1 in human cells that undergo polyploidization.Mol Biol Cell. 2002; 13: 3989-4000Crossref PubMed Scopus (42) Google Scholar]. CDK inhibitors (CDKi's) block the G1/S progression and belong to either the Cip/Kip (CDKN1) or the INK4 (CDKN2) family. MKs express both types of CDKi. All members of the CDKN1 family (p21CIP1/WAF1, p27Kip1, and p57KIP) are expressed [34Taniguchi T. Endo H. Chikatsu N. et al.Expression of p21(Cip1/Waf1/Sdi1) and p27(Kip1) cyclin-dependent kinase inhibitors during human hematopoiesis.Blood. 1999; 93: 4167-4178Crossref PubMed Google Scholar]; however, only p19INK4D expression increases linearly with polyploidization [35Raslova H. Kauffmann A. Sekkai D. et al.Interrelation between polyploidization and megakaryocyte differentiation: a gene profiling approach.Blood. 2007; 109: 3225-3234Crossref PubMed Scopus (0) Google Scholar]. It was initially thought that p21CIP1/WAF1 played a central role in polyploidization by licensing the G1/S progression at a low level and arresting endomitosis at a high level [36Kikuchi J. Furukawa Y. Iwase S. et al.Polyploidization and functional maturation are two distinct processes during megakaryocytic differentiation: involvement of cyclin-dependent kinase inhibitor p21 in polyploidization.Blood. 1997; 89: 3980-3990Crossref PubMed Google Scholar]. However, in homeostatic conditions, p21CIP1/WAF1 is dispensable because its knockout changes neither the platelet count nor the MK ploidy [37Baccini V. Roy L. Vitrat N. et al.Role of p21(Cip1/Waf1) in cell-cycle exit of endomitotic megakaryocytes.Blood. 2001; 98: 3274-3282Crossref PubMed Scopus (0) Google Scholar]. This is not related to a redundancy with p27Kip1 (unpublished results). The role of p57KIP2 is still unknown. However, in stress conditions, p21CIP1/WAF1is regulated by several signaling pathways, including mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription (STAT), protein regulator of cytokinesis-2 (PRC2), and p53, and its overexpression induces an arrest in endomitosis [37Baccini V. Roy L. Vitrat N. et al.Role of p21(Cip1/Waf1) in cell-cycle exit of endomitotic megakaryocytes.Blood. 2001; 98: 3274-3282Crossref PubMed Scopus (0) Google Scholar]. The role of p53 as a regulator of MK polyploidization has been ascertained. In basal conditions, p53-deficient MKs have no increased in ploidy [38Apostolidis P.A. Woulfe D.S. Chavez M. Miller W.M. Papoutsakis E.T. Role of tumor suppressor p53 in megakaryopoiesis and platelet function.Exp Hematol. 2012; 40 (e4): 131-142Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar], whereas stimulation induces a slight increase in ploidy and platelet level in p53-knockout mice. More importantly, p53 induces an arrest of endomitosis and apoptosis after a genotoxic stress. p19INK4D is presently the only CDKi that plays an important role in basal conditions. In mice, haploinsufficiency and knockout lead to a modal ploidy of 32N and 64N, respectively [39Gilles L. Guieze R. Bluteau D. et al.P19INK4D links endomitotic arrest and megakaryocyte maturation and is regulated by AML-1.Blood. 2008; 111: 4081-4091Crossref PubMed Scopus (0) Google Scholar]. This couples the arrest of endomitosis to MK terminal maturation because it is regulated transcriptionally by RUNX1 [39Gilles L. Guieze R. Bluteau D. et al.P19INK4D links endomitotic arrest and megakaryocyte maturation and is regulated by AML-1.Blood. 2008; 111: 4081-4091Crossref PubMed Scopus (0) Google Scholar]. When modeling the endocycle, it was initially suggested that cyclin B1, the expression and degradation of which are indispensable for mitosis entry and exit, respectively, was not expressed in MKs [29Wang Z. Zhang Y. Kamen D. Lees E. Ravid K. Cyclin D3 is essential for megakaryocytopoiesis.Blood. 1995; 86: 3783-3788PubMed Google Scholar]. However, further studies have shown that cyclin B1, as well as CDK1, are expressed in endomitotic MKs and are normally degraded by the anaphase-promoting complex including CDCD20 and CDH1 [21Vitrat N. Cohen-Solal K. Pique C. et al.Endomitosis of human megakaryocytes are due to abortive mitosis.Blood. 1998; 91: 3711-3723PubMed Google Scholar, 22Roy L. Coullin P. Vitrat N. et al.Asymmetrical segregation of chromosomes with a normal metaphase/anaphase checkpoint in polyploid megakaryocytes.Blood. 2001; 97: 2238-2247Crossref PubMed Scopus (0) Google Scholar, 40Zhang Y. Wang Z. Ravid K. The cell cycle in polyploid megakaryocytes is associated with reduced activity of cyclin B1-dependent cdc2 kinase.J Biol Chem. 1996; 271: 4266-4272Crossref PubMed Google Scholar]. The importance of cyclin B1 degradation has been underscored by Cdc20-null MKs, which are blocked in mitosis and undergo cell death [19Trakala M. Rodriguez-Acebes S. Maroto M. et al.Functional reprogramming of polyploidization in megakaryocytes.Dev Cell. 2015; 32: 155-167Abstract Full Text Full Text PDF PubMed Google Scholar]. Cdk1 knockout abrogates endomitosis, but not MK polyploidization, which is reprogrammed to endocycle [19Trakala M. Rodriguez-Acebes S. Maroto M. et al.Functional reprogramming of polyploidization in megakaryocytes.Dev Cell. 2015; 32: 155-167Abstract Full Text Full Text PDF PubMed Google Scholar]. Chromosome passenger proteins are normally expressed in MKs and are appropriately localized all along the endomitotic cell cycle [25Lordier L. Chang Y. Jalil A. et al.aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process.Blood. 2010; 116: 2345-2355Crossref PubMed Scopus (0) Google Scholar, 41Geddis A.E. Kaushansky K. Endomitotic megakaryocytes form a midzone in anaphase but have a deficiency in cleavage furrow formation.Cell Cycle. 2006; 5: 538-545Crossref PubMed Google Scholar]. It was suggested that aurora B, a kinase crucial for the metaphase/anaphase transition and cytokinesis, was not properly expressed in MKs [42Zhang Y. Nagata Y. Yu G. et al.Aberrant quantity and localization of aurora-B/AIM-1 and survivin during megakaryocyte polyploidization and the consequences of aurora-B/AIM-1-deregulated expression.Blood. 2004; 103: 3717-3726Crossref PubMed Scopus (0) Google Scholar, 43Kawasaki A. Matsumura I. Miyagawa J. et al.Downregulation of an AIM-1 kinase couples with megakaryocytic polyploidization of human hematopoietic cells.J Cell Biol. 2001; 152: 275-287Crossref PubMed Scopus (52) Google Scholar]. In fact, aurora B is expressed and localized normally in the centromeres at the beginning of endomitosis and later in the midzone, along with the other chromosome passenger proteins (survivin, INCENP, and borealin) [25Lordier L. Chang Y. Jalil A. et al.aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process.Blood. 2010; 116: 2345-2355Crossref PubMed Scopus (0) Google Scholar, 44Geddis A.E. Kaushansky K. Megakaryocytes express functional aurora-B kinase in endomitosis.Blood. 2004; 104: 1017-1024Crossref PubMed Scopus (0) Google Scholar]. As expected, aurora B phosphorylates its targets and localizes in the central spindle as well as RacGAP1/MgcRacGAP/Cyk4, an activator of ECT2, PRC1, and KIF4A [25Lordier L. Chang Y. Jalil A. et al.aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process.Blood. 2010; 116: 2345-2355Crossref PubMed Scopus (0) Google Scholar, 44Geddis A.E. Kaushansky K. Megakaryocytes express functional aurora-B kinase in endomitosis.Blood. 2004; 104: 1017-1024Crossref PubMed Scopus (0) Google Scholar]. Aurora B also plays an important role in abscission, but it is unknown whether the kinase is deactivated when abscission fails in endomitosis. Whereas functional inhibition of aurora B by chemical inhibitors or knockout does not inhibit MK polyploidization, maturation, or platelet production, it modifies the endomitotic process by skipping, not only cytokinesis, but also the late stages of mitosis [19Trakala M. Rodriguez-Acebes S. Maroto M. et al.Functional reprogramming of polyploidization in megakaryocytes.Dev Cell. 2015; 32: 155-167Abstract Full Text Full Text PDF PubMed Google Scholar, 25Lordier L. Chang Y. Jalil A. et al.aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process.Blood. 2010; 116: 2345-2355Crossref PubMed Scopus (0) Google Scholar]. Therefore, a true physiological endomitosis is not necessary for MK polyploidization and platelet production because either an abnormal endomitosis (aurora B deficiency) [25Lordier L. Chang Y. Jalil A. et al.aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process.Blood. 2010; 116: 2345-2355Crossref PubMed Scopus (0) Google Scholar] or reprogramming the cell cycle to endocycle leads to completely functional polyploid MKs [19Trakala M. Rodriguez-Acebes S. Maroto M. et al.Functional reprogramming of polyploidization in megakaryocytes.Dev Cell. 2015; 32: 155-167Abstract Full Text Full Text PDF PubMed Google Scholar]. Polo-like kinase 1 (PLK1) regulates centrosome maturation, mitosis entry, spindle formation, and cytokinesis and is indispensable for MK polyploidization [45Trakala M. Partida D. Salazar-Roa M. et al.Activation of the endomitotic spindle assembly checkpoint and thrombocytopenia in Plk1-deficient mice.Blood. 2015; 126: 1707-1714Crossref PubMed Scopus (2) Google Scholar]. Its knockout leads to endomitotic arrest and induces the spindle assembly checkpoint [45Trakala M. Partida D. Salazar-Roa M. et al.Activation of the endomitotic spindle assembly checkpoint and thrombocytopenia in Plk1-deficient mice.Blood. 2015; 126: 1707-1714Crossref PubMed Scopus (2) Google Scholar]. Aurora A shares functional similitudes with PLK1 on centrosomes and spindle formation. It is necessary during normal mitosis, but is dispensable for endomitosis [46Goldenson B. Kirsammer G. Stankiewicz M.J. Wen Q.J. Crispino J.D. aurora kinase A is required for hematopoiesis but is dispensable for murine megakaryocyte endomitosis and differentiation.Blood. 2015; 125: 2141-2150Crossref PubMed Scopus (9) Google Scholar]. Furthermore, inhibition of aurora A increases MK polyploidization [47Wen Q. Goldenson B. Silver S.J. et al.Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL.Cell. 2012; 150: 575-589Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar] and the differentiation of MK leukemic cells [47Wen Q. Goldenson B. Silver S.J. et al.Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL.Cell. 2012; 150: 575-589Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 48Wen Q.J. Yang Q. Goldenson B. et al.Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition.Nat Med. 2015; 21: 1473-1480Crossref PubMed Scopus (23) Google Scholar]. This simultaneous induction of polyploidization and maturation by aurora A inhibition suggests that aurora A may target the phosphorylation/activation of an MK TF. A schematic illustration of the cell cycle regulation is shown in Fig. 5. The main regulator of cleavage furrow formation and ingression is the RhoA pathway, which permits the formation of an actomyosin ring necessary to generate the contractile forces for cell separation (abscission). Activation of RhoA at the cleavage furrow induces local actin polymerization, myosin II accumulation, and activation, which allows the progression of the furrow and permits abscission. This is mediated for F actin by the formin/profilin machine and for myosin activation through phosphorylation of the myosin light chain (MLC2) by ROCK and citron kinase. In endomitosis, there is a defect both in myosin and F actin accumulation, with a residual myosin activity [24Lordier L. Jalil A. Aurade F. et al." @default.
• W2767020540 created "2017-11-10" @default.
• W2767020540 creator A5009104683 @default.
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• W2767020540 creator A5071767949 @default.
• W2767020540 date "2018-01-01" @default.
• W2767020540 modified "2023-10-12" @default.
• W2767020540 title "Megakaryocyte and polyploidization" @default.
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