Megakaryocyte Polyploidization in May-Hegglin Anomaly

Mayer, Miroslav; Sperling, Harry G.; Schaefer, Jennifer; Queißer, W.

doi:10.1159/000207694

Cited by 8 publications

(6 citation statements)

References 3 publications

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“…These individuals have either a normal or an increased number of megakaryocytes 6,15-17 and normal megakaryocyte DNA ploidy. 16,18 Recently, 2 separate in vitro studies using megakaryocytes differentiated from mouse embryonic stem cells or human CD34 ϩ cells described the involvement of the Rho-Rho kinase-MLC-myosin IIA pathway in proplatelet formation. 19,20 Inhibition of this pathway at either level resulted in enhanced proplatelet formation, suggesting myosin to be a negative regulator of platelet production.…”

Section: Introductionmentioning

confidence: 99%

“…13,14 The role of myosin IIA in platelet biogenesis is still poorly understood and only a few reports are available concerning the impact of myosin IIA mutations on the bone marrow megakaryocytes of MYH9-RD patients. These individuals have either a normal or an increased number of megakaryocytes 6,[15][16][17] and normal megakaryocyte DNA ploidy. 16,18 Recently, 2 separate in vitro studies using megakaryocytes differentiated from mouse embryonic stem cells or human CD34 ϩ cells described the involvement of the Rho-Rho kinase-MLC-myosin IIA pathway in proplatelet formation.…”

Section: Introductionmentioning

confidence: 99%

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Abnormal megakaryocyte morphology and proplatelet formation in mice with megakaryocyte-restricted MYH9 inactivation

Eckly

Strassel

Freund

et al. 2009

Blood

102

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Mutations in the MYH9 gene encoding nonmuscle myosin IIA lead to macrothrombocytopenia as observed in MYH9-related disorders. We used mice with megakaryocyterestricted MYH9 inactivation to explore the role of myosin in thrombopoiesis. In situ, bone marrow MYH9⌬ megakaryocytes were irregularly shaped, appearing leaky with poorly defined limits. The demarcation membranes were abnormally organized and poorly developed, pointing to an insufficient reservoir for the future formation of platelets. The cytoskeletal-rich peripheral zone was lacking due to the absence of the myosin filament network that normally surrounds the granular zone in wild-type cells. In vitro studies of cultured cells showed that MYH9⌬ megakaryocytes were unable to form stress fibers upon adhesion to collagen, suggesting that the leaky shape results from defects in internal tension and anchorage to the extracellular environment. Surprisingly, the proportion of cells extending proplatelets was increased in MYH9⌬ megakaryocytes and the proplatelet buds were larger. Overall, this study provides evidence for a role of myosin in different steps of megakaryocyte development through its participation in the maintenance of cell shape, formation and organization of the demarcation membranes and the peripheral zone, anchorage to the extracellular matrix, and proplatelet formation. IntroductionNonmuscle myosin IIA plays a fundamental role in basic cellular functions such as cell division, adhesion to extracellular matrices, and migration. 1 The myosin IIA heavy chain is encoded by the MYH9 gene and is the only isoform of nonmuscle myosin II present in blood platelets, unlike most cells that also express myosin IIB. 2 Mutations in the MYH9 gene lead to dominant hereditary hemorrhagic diseases known as MYH9-related disorders (MYH9-RD, previously classified as the May-Hegglin anomaly and the syndromes of Sebastian, Fechtner, and Epstein) characterized by congenital thrombocytopenia with large platelets (macrothrombocytopenia) and leukocyte inclusions, sometimes associated with loss of hearing, cataracts, or nephritis during childhood and/or adulthood. 3,4 The origin of the thrombocytopenia is unknown but most probably results from defective thrombopoiesis since the platelet half-life appears to be either normal or only slightly decreased in these patients. 5,6 Blood platelets are produced by megakaryocytes following differentiation and maturation of hematopoietic stem cells into giant polyploid cells. 7,8 The ultrastructure of these mature megakaryocytes reveals a large and highly organized cytoplasm. 9,10 The granular zone contains an extensive membrane network called the demarcation membrane system (DMS) that constitutes a membrane reservoir for the future platelets, 11 whereas the actinrich peripheral zone is devoid of DMS and organelles. 9,10,12 It is now thought that mature megakaryocytes release platelets through extension of cytoplasmic projections, the so-called proplatelets, into the vessel lumen. 13,14 The role of myosin IIA in platelet biogenesis ...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Abnormal megakaryocyte morphology and proplatelet formation in mice with megakaryocyte-restricted MYH9 inactivation

Eckly

Strassel

Freund

et al. 2009

Blood

102

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“…An abnormal production had been suspected [10,17,18]. Davis and Wilson [7] found a decreased platelet life-span which seems to indicate peri pherally increased platelet destruction.…”

Section: Discussionmentioning

confidence: 99%

Hereditary Nephritis Associated with May-Hegglin Anomaly

Brivet

Girot

Barbanel³

et al. 1981

Nephron

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Hereditary nephritis associated with hematologic abnormalities seems to be an exceptional occurrence. We have observed a family in which nephritis was combined with May-Hegglin anomaly. A girl and her father suffered from proteinuria; a paternal uncle received a kidney graft; a paternal grand aunt died on periodic hemodialysis. The girl, the father and the uncle presented macrothrombocytopenia (40–100 × 10⁹/l, size 4–8 µm) with prolonged bleeding time (which precluded renal biopsy) and cytoplasmic inclusions in neutrophils (Döhle bodies). These hematologic abnormalities characterize the May-Hegglin anomaly. This kind of association has not been reported on so far.

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“…The following tests were performed: platelet aggregation (22), platelet factor 3 availability, bleeding and clotting times, clot retraction time, one stage prothrombin time (20), partial thromboplastin time (23), assay of fibrinogen (24) and FDk (25). , l"/" sodium deoxycholate (DOC),2 mM PMSF (5 x 107 cells/1.5 ml), and then sonicated.…”

Section: Patients and General Proceduresmentioning

confidence: 99%

“…On the other hand with the immunoprecipitation the specific antiserum precipitated all the tive major fractions of normal membrane glycoproteins, but it was shown to react quite poorly with the component V of the May-Hegglin glycoprotein pattern. lntroduction May-Hegglin anomaly (1) is a rare autosomal-dominant condition charact erized by thrombocytopenia, giant platelets, and cytoplasmic inclusions in the polymorphonuclear leucocytes (2)(3)(4)(5)(6). In spite of the presence of normal platelet function tests, some patients affected by this anomaly may undergo bleeding.…”

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confidence: 99%

Evidence for Glycoprotein Abnormality in Platelets from Patients with May-Hegglin Anomaly

et al. 1985

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SummaryIn the present research protein analysis on SDS-polyacry-lamide gel electrophoresis (PAGE) has been used to study the glycoprotein pattern of the blood platelets of four members from a family affected by May-Hegglin anomaly. In order to characterize the glycoprotein fractions, lactoperoxidase-iodination and immunoprecipitation procedures were used.N,N’diallyltartardiamide (DATD) cross-linked gel electrophoresis was shown to improve the glycoprotein pattern resolution, although with the lactoperoxidase-iodination the glycoprotein characterization of May-Hegglin platelets overlapped the normal. On the other hand with the immunoprecipitation the specific antiserum precipitated all the five major fractions of normal membrane glycoproteins, but it was shown to react quite poorly with the component V of the May-Hegglin glycoprotein pattern.

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Megakaryocyte Polyploidization in May-Hegglin Anomaly

Cited by 8 publications

References 3 publications

Abnormal megakaryocyte morphology and proplatelet formation in mice with megakaryocyte-restricted MYH9 inactivation

Abnormal megakaryocyte morphology and proplatelet formation in mice with megakaryocyte-restricted MYH9 inactivation

Hereditary Nephritis Associated with May-Hegglin Anomaly

Evidence for Glycoprotein Abnormality in Platelets from Patients with May-Hegglin Anomaly

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