Historical review: megakaryopoiesis and thrombopoiesis

Kaushansky, Kenneth

doi:10.1182/blood-2007-05-088500

Cited by 276 publications

(247 citation statements)

References 76 publications

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“…Proplatelet formation requires profound changes in the organization of the cytoskeleton, which are regulated by several transcription factors required for the megakaryocytic differentiation program. These transcription factors are including GATA1, GATA2, and NF-E2 [23]. Indeed, upon DAC exposure, we observed an increase of GATA2…”

Section: Page 17 Of 59mentioning

confidence: 67%

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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Section: Page 17 Of 59mentioning

confidence: 67%

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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“…Megakaryopoiesis and platelet formation are governed by hematopoietic growth factors. Thrombopoietin (TPO) is the principal regulator of megakaryopoiesis, affecting self‐renewal and expansion of hematopoietic stem cells, proliferation of megakaryocyte progenitors, and supporting their maturation into platelet‐producing cells 14. Other contributing mediators are stem cell factor, stromal‐derived factor 1, and interleukins 3, 6, and 11.…”

Section: Introductionmentioning

confidence: 99%

Iron deficiency alters megakaryopoiesis and platelet phenotype independent of thrombopoietin

et al. 2014

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Iron deficiency is a common cause of reactive thrombocytosis, however, the exact pathways have not been revealed. Here we aimed to study the mechanisms behind iron deficiency‐induced thrombocytosis. Within few weeks, iron‐depleted diet caused iron deficiency in young Sprague–Dawley rats, as reflected by a drop in hemoglobin, mean corpuscular volume, hepatic iron content and hepcidin mRNA in the liver. Thrombocytosis established in parallel. Moreover, platelets produced in iron deficient animals displayed a higher mean platelet volume and increased aggregation. Bone marrow studies revealed subtle alterations that are suggestive of expansion of megakaryocyte progenitors, an increase in megakaryocyte ploidy and accelerated megakaryocyte differentiation. Iron deficiency did not alter the production of hematopoietic growth factors such as thrombopoietin, interleukin 6 or interleukin 11. Megakaryocytic cell lines grown in iron‐depleted conditions exhibited reduced proliferation but increased ploidy and cell size. Our data suggest that iron deficiency increases megakaryopoietic differentiation and alters platelet phenotype without changes in megakaryocyte growth factors, specifically TPO. Iron deficiency‐induced thrombocytosis may have evolved to maintain or increase the coagulation capacity in conditions with chronic bleeding. Am. J. Hematol. 89:524–529, 2014. © 2014 Wiley Periodicals, Inc.

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“…P latelets, the blood cells involved in haemostasis, arise in mammals from the fragmentation of the cytoplasm of a giant cell called megakaryocyte (MK) 1,2 . The large cell size is related to polyploidization, a unique process that is an integral part of MK differentiation 3 .…”

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confidence: 99%

RUNX1-induced silencing of non-muscle myosin heavy chain IIB contributes to megakaryocyte polyploidization

et al. 2012

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megakaryocytes are unique mammalian cells that undergo polyploidization (endomitosis) during differentiation, leading to an increase in cell size and protein production that precedes platelet production. Recent evidence demonstrates that endomitosis is a consequence of a late failure in cytokinesis associated with a contractile ring defect. Here we show that the non-muscle myosin IIB heavy chain (mYH10) is expressed in immature megakaryocytes and specifically localizes in the contractile ring. mYH10 downmodulation by short hairpin RnA increases polyploidization by inhibiting the return of 4n cells to 2n, but other regulators, such as of the G1/s transition, might regulate further polyploidization of the 4n cells. Conversely, re-expression of mYH10 in the megakaryocytes prevents polyploidization and the transition of 2n to 4n cells. During polyploidization, mYH10 expression is repressed by the major megakaryocyte transcription factor RunX1. Thus, RunX1-mediated silencing of mYH10 is required for the switch from mitosis to endomitosis, linking polyploidization with megakaryocyte differentiation.

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Historical review: megakaryopoiesis and thrombopoiesis

Cited by 276 publications

References 76 publications

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

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

Iron deficiency alters megakaryopoiesis and platelet phenotype independent of thrombopoietin

RUNX1-induced silencing of non-muscle myosin heavy chain IIB contributes to megakaryocyte polyploidization

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