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Poster Sessions| November 16, 2004

Visualization of c-Mpl Expression in Ph-Negative Myeloproliferative Diseases and So-Called Essential Thrombocythemia with Ringed Sideroblasts by Confocal Laser Scanning Microscopy.

Annette Schmitt-Graeff, MD,

Annette Schmitt-Graeff, MD *

¹of Pathology, Universityhospital of Freiburg, Freiburg, Germany; ²of Pathology, University of Cologne, Cologne, Germany; ³of Pathology, University of Cologne, Cologne, Germany; ⁴of Hematology, Oncology and Immunology, University of Düsseldorf, Duesseldorf, Germany; ⁵of Medicine, Division of Hematology and Oncology, Universityhospital of Freiburg, Freiburg, Germany; ⁶of medicine, Division of Hematology and Oncology, Universityhospital Freiburg, Freiburg, Germany; ⁷of Biology II, University of Freiburg, Freiburg, Germany; ⁸of Biology II, University of Freiburg, Freiburg, Germany; ⁹of Experimental Anaesthesiology, Universityhospital of Freiburg, Freiburg, Germany and ¹⁰Hematology Division, John Hopkins University School of Medicine, Baltimore, USA.

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Juergen Thiele, MD,

Juergen Thiele, MD *

¹of Pathology, Universityhospital of Freiburg, Freiburg, Germany; ²of Pathology, University of Cologne, Cologne, Germany; ³of Pathology, University of Cologne, Cologne, Germany; ⁴of Hematology, Oncology and Immunology, University of Düsseldorf, Duesseldorf, Germany; ⁵of Medicine, Division of Hematology and Oncology, Universityhospital of Freiburg, Freiburg, Germany; ⁶of medicine, Division of Hematology and Oncology, Universityhospital Freiburg, Freiburg, Germany; ⁷of Biology II, University of Freiburg, Freiburg, Germany; ⁸of Biology II, University of Freiburg, Freiburg, Germany; ⁹of Experimental Anaesthesiology, Universityhospital of Freiburg, Freiburg, Germany and ¹⁰Hematology Division, John Hopkins University School of Medicine, Baltimore, USA.

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Hans M. Kvasnicka, MD,

Hans M. Kvasnicka, MD *

¹of Pathology, Universityhospital of Freiburg, Freiburg, Germany; ²of Pathology, University of Cologne, Cologne, Germany; ³of Pathology, University of Cologne, Cologne, Germany; ⁴of Hematology, Oncology and Immunology, University of Düsseldorf, Duesseldorf, Germany; ⁵of Medicine, Division of Hematology and Oncology, Universityhospital of Freiburg, Freiburg, Germany; ⁶of medicine, Division of Hematology and Oncology, Universityhospital Freiburg, Freiburg, Germany; ⁷of Biology II, University of Freiburg, Freiburg, Germany; ⁸of Biology II, University of Freiburg, Freiburg, Germany; ⁹of Experimental Anaesthesiology, Universityhospital of Freiburg, Freiburg, Germany and ¹⁰Hematology Division, John Hopkins University School of Medicine, Baltimore, USA.

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Ulrich Germing, MD,

Ulrich Germing, MD *

¹of Pathology, Universityhospital of Freiburg, Freiburg, Germany; ²of Pathology, University of Cologne, Cologne, Germany; ³of Pathology, University of Cologne, Cologne, Germany; ⁴of Hematology, Oncology and Immunology, University of Düsseldorf, Duesseldorf, Germany; ⁵of Medicine, Division of Hematology and Oncology, Universityhospital of Freiburg, Freiburg, Germany; ⁶of medicine, Division of Hematology and Oncology, Universityhospital Freiburg, Freiburg, Germany; ⁷of Biology II, University of Freiburg, Freiburg, Germany; ⁸of Biology II, University of Freiburg, Freiburg, Germany; ⁹of Experimental Anaesthesiology, Universityhospital of Freiburg, Freiburg, Germany and ¹⁰Hematology Division, John Hopkins University School of Medicine, Baltimore, USA.

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Michael Luebbert, MD,

Michael Luebbert, MD *

¹of Pathology, Universityhospital of Freiburg, Freiburg, Germany; ²of Pathology, University of Cologne, Cologne, Germany; ³of Pathology, University of Cologne, Cologne, Germany; ⁴of Hematology, Oncology and Immunology, University of Düsseldorf, Duesseldorf, Germany; ⁵of Medicine, Division of Hematology and Oncology, Universityhospital of Freiburg, Freiburg, Germany; ⁶of medicine, Division of Hematology and Oncology, Universityhospital Freiburg, Freiburg, Germany; ⁷of Biology II, University of Freiburg, Freiburg, Germany; ⁸of Biology II, University of Freiburg, Freiburg, Germany; ⁹of Experimental Anaesthesiology, Universityhospital of Freiburg, Freiburg, Germany and ¹⁰Hematology Division, John Hopkins University School of Medicine, Baltimore, USA.

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Cornelius Waller, MD,

Cornelius Waller, MD *

¹of Pathology, Universityhospital of Freiburg, Freiburg, Germany; ²of Pathology, University of Cologne, Cologne, Germany; ³of Pathology, University of Cologne, Cologne, Germany; ⁴of Hematology, Oncology and Immunology, University of Düsseldorf, Duesseldorf, Germany; ⁵of Medicine, Division of Hematology and Oncology, Universityhospital of Freiburg, Freiburg, Germany; ⁶of medicine, Division of Hematology and Oncology, Universityhospital Freiburg, Freiburg, Germany; ⁷of Biology II, University of Freiburg, Freiburg, Germany; ⁸of Biology II, University of Freiburg, Freiburg, Germany; ⁹of Experimental Anaesthesiology, Universityhospital of Freiburg, Freiburg, Germany and ¹⁰Hematology Division, John Hopkins University School of Medicine, Baltimore, USA.

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Sabine Haxelmanns,

Sabine Haxelmanns *

¹of Pathology, Universityhospital of Freiburg, Freiburg, Germany; ²of Pathology, University of Cologne, Cologne, Germany; ³of Pathology, University of Cologne, Cologne, Germany; ⁴of Hematology, Oncology and Immunology, University of Düsseldorf, Duesseldorf, Germany; ⁵of Medicine, Division of Hematology and Oncology, Universityhospital of Freiburg, Freiburg, Germany; ⁶of medicine, Division of Hematology and Oncology, Universityhospital Freiburg, Freiburg, Germany; ⁷of Biology II, University of Freiburg, Freiburg, Germany; ⁸of Biology II, University of Freiburg, Freiburg, Germany; ⁹of Experimental Anaesthesiology, Universityhospital of Freiburg, Freiburg, Germany and ¹⁰Hematology Division, John Hopkins University School of Medicine, Baltimore, USA.

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Roland Nitschke, Ph.D,

Roland Nitschke, Ph.D *

¹of Pathology, Universityhospital of Freiburg, Freiburg, Germany; ²of Pathology, University of Cologne, Cologne, Germany; ³of Pathology, University of Cologne, Cologne, Germany; ⁴of Hematology, Oncology and Immunology, University of Düsseldorf, Duesseldorf, Germany; ⁵of Medicine, Division of Hematology and Oncology, Universityhospital of Freiburg, Freiburg, Germany; ⁶of medicine, Division of Hematology and Oncology, Universityhospital Freiburg, Freiburg, Germany; ⁷of Biology II, University of Freiburg, Freiburg, Germany; ⁸of Biology II, University of Freiburg, Freiburg, Germany; ⁹of Experimental Anaesthesiology, Universityhospital of Freiburg, Freiburg, Germany and ¹⁰Hematology Division, John Hopkins University School of Medicine, Baltimore, USA.

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Heike L. Pahl, Ph.D,

Heike L. Pahl, Ph.D

¹of Pathology, Universityhospital of Freiburg, Freiburg, Germany; ²of Pathology, University of Cologne, Cologne, Germany; ³of Pathology, University of Cologne, Cologne, Germany; ⁴of Hematology, Oncology and Immunology, University of Düsseldorf, Duesseldorf, Germany; ⁵of Medicine, Division of Hematology and Oncology, Universityhospital of Freiburg, Freiburg, Germany; ⁶of medicine, Division of Hematology and Oncology, Universityhospital Freiburg, Freiburg, Germany; ⁷of Biology II, University of Freiburg, Freiburg, Germany; ⁸of Biology II, University of Freiburg, Freiburg, Germany; ⁹of Experimental Anaesthesiology, Universityhospital of Freiburg, Freiburg, Germany and ¹⁰Hematology Division, John Hopkins University School of Medicine, Baltimore, USA.

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Jerry L. Spivak, MD, Ph.D.

Jerry L. Spivak, MD, Ph.D.

¹of Pathology, Universityhospital of Freiburg, Freiburg, Germany; ²of Pathology, University of Cologne, Cologne, Germany; ³of Pathology, University of Cologne, Cologne, Germany; ⁴of Hematology, Oncology and Immunology, University of Düsseldorf, Duesseldorf, Germany; ⁵of Medicine, Division of Hematology and Oncology, Universityhospital of Freiburg, Freiburg, Germany; ⁶of medicine, Division of Hematology and Oncology, Universityhospital Freiburg, Freiburg, Germany; ⁷of Biology II, University of Freiburg, Freiburg, Germany; ⁸of Biology II, University of Freiburg, Freiburg, Germany; ⁹of Experimental Anaesthesiology, Universityhospital of Freiburg, Freiburg, Germany and ¹⁰Hematology Division, John Hopkins University School of Medicine, Baltimore, USA.

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Blood (2004) 104 (11): 2440.

https://doi.org/10.1182/blood.V104.11.2440.2440

Abstract

c-Mpl acts as a primary regulator of megakaryocytopoiesis and platelet production and is essential for the maintenance of normal hematopoiesis in humans. An impaired posttranslational processing of Mpl with underglycosylation has been proposed as a molecular defect of polycythemia vera (PV) and chronic idiopathic myelofibrosis (

CIMF; Molinterno and Spivak, Blood 1999; 94: 2555

).

To visualize the subcellular localization of megakaryocyte c-Mpl protein in myeloproliferative diseases and myelodysplastic/myeloproliferative disorders we performed an imaging study by confocal laser scanning microscopy. Bone marrow trephines from normal bone marrow donors (n=14), patients with essential thrombocythemia (ET, n=15), PV (n=18), CIMF (n=15), myelodysplastic syndromes (MDS) including refractory anemia with ringed sideroblasts (RS; n=12) and so-called essential thrombocythemia with RS (ET/RS; n=67) were examined. Immunohistochemistry was performed using a rabbit polyclonal antibody recognizing glycosylated and unglycosylated c-Mpl and semiquantitatively evaluated by scoring of plasmalemmal vs. cytoplasmic labeling (score 1–3).

Our results provide evidence that normal megakaryocytes show a pronounced cell surface expression of c-Mpl. In PV and CIMF, c-Mpl suface expression was significantly reduced (p<0.001), while cytoplasmic expression was often strongly accentuated. In ET, heterogeneous patterns of membraneous labeling were observed ranging from normal to decreased. In MDS, plasmalemmal immunoreacativity was generally down-regulated. In ET/RS c-Mpl imaging revealed a heterogeneous positivity with different degrees of plasmalemmal vs. cytoplasmic immunoreactivity in keeping either with CIMF, true ET or MDS.

The role of c-Mpl as a biomarker of Ph-negative MPDs is controversely discussed. A weak megakaryocyte c-Mpl staining which may complement morphologic distinction has been observed in PV (

Tefferi et al., Blood 2000; 96: 771

). Our findings suggest that the strikingly reduced cell surface c-Mpl expression despite equivalent or increased mRNA levels (

Bock et al., J Pathol 2004; 203: 609

) may result in impaired receptor domains for TPO in PV and CIMF and is a characteristic epigenetic abnormality of theses entities. Upon consideration of all our clinico-pathological data, so-called ET/RS is now fracturing in clearly defined haematological diseases which could be categorized as CIMF/RS (38/67), true ET/RS (10/67) or different MDS categories (n=19). The heterogeneous patterns of c-Mpl expression further contribute to define positive criteria for the discrimination of the distinct entities within in the ET/RS group.

Author notes

Corresponding author

2005, The American Society of Hematology

2004

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