Megakaryocytic dysfunction in myelodysplastic syndromes and idiopathic thrombocytopenic purpura is in part due to different forms of cell death

Houwerzijl, Ewout J.; Blom, Nel R.; Want, J.J.L. van der; Vellenga, Edo; Wolf, de Joseph

doi:10.1038/sj.leu.2404385

Cited by 56 publications

(39 citation statements)

References 47 publications

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“…on May 10, 2018. by guest www.bloodjournal.org From including necrosis, apoptosis, and para-apoptosis have been used to describe the various processes observed. 36 In comparing our observations with those published, it is interesting to note that megakaryocytes in ITP patients 33 share features similar to those of dying Mcl-1 Pf4⌬/Pf4⌬ cells. Thus, in addition to the established role of Bak/Bax-mediated apoptosis in mediating chemotherapy-induced thrombocytopenia, 9 it is possible activation of the intrinsic pathway plays a role in other disorders associated with impaired platelet production.…”

Section: Discussionsupporting

confidence: 63%

Mcl-1 and Bcl-xL coordinately regulate megakaryocyte survival

Debrincat

Josefsson

James

et al. 2012

Blood

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Mature megakaryocytes depend on the function of Bcl-x L , a member of the Bcl-2 family of prosurvival proteins, to proceed safely through the process of platelet shedding. Despite this, loss of Bcl-x L does not prevent the growth and maturation of megakaryocytes, suggesting redundancy with other prosurvival proteins. We therefore generated mice with a megakaryocyte-specific deletion of Mcl-1, which is known to be expressed in megakaryocytes. Megakaryopoiesis, platelet production, and platelet lifespan were unperturbed in Mcl IntroductionMegakaryocytes are large polyploid cells responsible for the production of blood platelets. They develop primarily in the BM and spleen. On reaching maturity, megakaryocytes extend long pseudopodial projections called proplatelets into the circulation, and it is from these structures that platelets are released. [1][2][3] Once born, platelets have a brief lifespan in the circulation: 10 days in humans, 5 days in mice. 4,5 In recent years, it has become apparent that this finite existence is governed by the interplay between members of the Bcl-2 protein family, the critical regulators of the "intrinsic" or "mitochondrial" apoptosis pathway. 6 Platelets depend on the prosurvival protein Bcl-x L to maintain their viability. 7 Mutations in murine Bcl-x L cause dose-dependent cell-intrinsic reductions in platelet lifespan. 7-9 Pharmacologic blockade of Bcl-x L with the BH3 mimetic drugs ABT-737 10 or ABT-263 11 triggers platelet death 7,12-15 and thrombocytopenia in mice, 7,16 dogs, 15 and humans. 17,18 The function of Bcl-x L is to restrain the prodeath proteins Bak and Bax. When activated, Bak and Bax induce mitochondrial outer membrane permeabilization (MOMP), resulting in platelet apoptosis, which, at least in vitro, is characterized by cytochrome c release, caspase activation, and phosphatidylserine exposure. [12][13][14][15] At steady state in vivo, aged platelets that have escaped hemostatic consumption undergo Bak-mediated apoptosis and clearance from the circulation. Genetic deletion of Bak and Bax almost doubles platelet lifespan, 9 rescues the thrombocytopenia caused by loss of Bcl-x L , 9 and renders platelets refractory to the effects of ABT-737. 13 We recently demonstrated that Bcl-x L is also essential for mature megakaryocytes to proceed safely through the process of platelet shedding. 9 In vitro, loss of Bcl-x L triggers Bak-and Bax-mediated mitochondrial damage, caspase activation, and failure of proplatelet formation. In vivo, mature, shedding megakaryocytes lacking Bcl-x L exhibit severe dysmorphology and produce grossly abnormal platelets that survive only hours in the circulation. Bcl-x L is, however, dispensable for the growth and development of megakaryocytes, suggesting that other Bcl-2 family prosurvival proteins are necessary to promote survival during this process. Of the 5 prosurvival members of the Bcl-2 family, 6 3 are known to be expressed in megakaryocytes: Bcl-2, Bcl-x L , and Mcl-1. 9 Given its critical role in hematopoietic progenitors and lymphocy...

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Section: Discussionsupporting

confidence: 63%

Mcl-1 and Bcl-xL coordinately regulate megakaryocyte survival

Debrincat

Josefsson

James

et al. 2012

Blood

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“…Apoptosis of dysplastic megakaryocytes and shortened platelet life expectancy in the BM, 51,52 together with a decreased platelet release by the dysplastic megakaryocytic precursors 53 reported in MDS, might contribute to explain the absence of an altered platelet immunophenotype in these cases, because under these conditions a normal immunophenotypic score may result from the immunophenotypic analysis of residual normal, rather than dysplastic, PB platelets.…”

Section: Discussionmentioning

confidence: 98%

Altered immunophenotypic features of peripheral blood platelets in myelodysplastic syndromes

Sandes¹,

Yamamoto²,

Matarraz³

et al. 2012

Haematologica

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BackgroundMultiparameter flow cytometric analysis of bone marrow and peripheral blood cells has proven to be of help in the diagnostic workup of myelodysplastic syndromes. However, the usefulness of flow cytometry for the detection of megakaryocytic and platelet dysplasia has not yet been investigated. The aim of this pilot study was to evaluate by flow cytometry the diagnostic and prognostic value of platelet dysplasia in myelodysplastic syndromes. Design and MethodsWe investigated the pattern of expression of distinct surface glycoproteins on peripheral blood platelets from a series of 44 myelodysplastic syndrome patients, 20 healthy subjects and 19 patients with platelet alterations associated to disease conditions other than myelodysplastic syndromes. Quantitative expression of CD31, CD34, CD36, CD41a, CD41b, CD42a, CD42b and CD61 glycoproteins together with the PAC-1, CD62-P, fibrinogen and CD63 platelet activation-associated markers and platelet light scatter properties were systematically evaluated. ResultsOverall, flow cytometry identified multiple immunophenotypic abnormalities on platelets of myelodysplastic syndrome patients, including altered light scatter characteristics, over-and under expression of specific platelet glycoproteins and asynchronous expression of CD34; decreased expression of CD36 (n=5), CD42a (n=1) and CD61 (n=2), together with reactivity for CD34 (n=1) were only observed among myelodysplastic syndrome cases, while other alterations were also found in other platelet disorders. Based on the overall platelet alterations detected for each patient, an immunophenotypic score was built which identified a subgroup of myelodysplastic syndrome patients with a high rate of moderate to severe alterations (score>1.5; n=16) who more frequently showed thrombocytopenia, megakaryocytic dysplasia and high-risk disease, together with a shorter overall survival. ConclusionsOur results show the presence of altered phenotypes by flow cytometry on platelets from around half of the myelodysplastic syndrome patients studied. If confirmed in larger series of patients, these findings may help refine the diagnostic and prognostic assessment of this group of disorders.

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“…30 Houwerzijl et al also reported that morphology compatible with para-apoptosis could be induced in cultured megakaryocytes with ITP plasma. 31 Whether para-apoptosis mediated megakaryocyte destruction was induced by autoantibody requires further investigation. Moreover, as with 2 important cyclins in megakaryocyte development and high ploidy formation, 32 the absence of cyclin D3 during the whole culture and low expression of cyclin B1 at early stage may have been the mechanism by which patient IgG inhibited megakaryocyte polyploidization.…”

Section: Discussionmentioning

confidence: 99%

“…Local caspase activation can lead to proplatelet formation and thus platelet release. 16,18,35 Houwerzijl et al 31 have reported that the inhibited megakaryocyte apoptosis may contribute to thrombocytopenia and augment dysfunctional megakaryocytes. We found reduced megakaryocyte apoptosis in the boosted megakaryocyte group, indicating that the reduced megakaryocyte apoptosis could be associated with a boosted megakaryocyte mass, but an impaired megakaryocyte maturation and reduced platelet production.…”

Section: Discussionmentioning

confidence: 99%

Contributions of TRAIL-mediated megakaryocyte apoptosis to impaired megakaryocyte and platelet production in immune thrombocytopenia

Yang

Wang

Zhao

et al. 2010

Blood

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Recent in vitro studies provide evidence for autoantibody-induced suppression of megakaryocytopoiesis and show a reduction in megakaryocyte production and maturation in the presence of immune thrombocytopenia (ITP) plasma. Here, we present CD34 ؉ cells from healthy umbilical cord blood mononuclear cells cultured in medium containing thrombopoietin, stem cell factor, interleukin-3, and 10% plasma from either ITP patients or healthy subjects. The quantity, quality, and apoptosis of megakaryocytes were measured. We observed that most ITP plasma boosted megakaryocyte quantity but impaired quality, resulting in significantly less polyploidy cells (N > 4) and platelet release. In these megakaryocytes, we found a lower percentage of cell apoptosis, a lower expression of tumor necrosis factor-related apoptosisinducing ligand (TRAIL), and a higher expression of Bcl-xL.

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Megakaryocytic dysfunction in myelodysplastic syndromes and idiopathic thrombocytopenic purpura is in part due to different forms of cell death

Cited by 56 publications

References 47 publications

Mcl-1 and Bcl-xL coordinately regulate megakaryocyte survival

Mcl-1 and Bcl-xL coordinately regulate megakaryocyte survival

Altered immunophenotypic features of peripheral blood platelets in myelodysplastic syndromes

Contributions of TRAIL-mediated megakaryocyte apoptosis to impaired megakaryocyte and platelet production in immune thrombocytopenia

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