An increased bone marrow (BM) apoptosis is one of the mechanisms responsible for the ineffective hematopoiesis of myelodysplastic syndromes (MDS). It is controversial whether the excessive apoptosis in myelodysplasia predominantly involves the subset of progenitor cells or of maturing cells. We investigated the degree of apoptosis in MDS BM and its differences from normal marrow in relation to CD34 antigen expression. A double-labelling technique that combined the Tdt-mediated dUTP nick end labelling (TUNEL) method with immunocytochemistry for CD34 antigen was used on BM slides of 18 MDS patients and 11 controls. The apoptotic rate (AR) appeared significantly higher in CD34-negative than in CD34-positive cell subsets both in myelodysplastic and in normal BM. When MDS and normal CD34-negative cell populations were compared, a greater AR in MDS CD34-negative cells was found, while no statistical difference in AR resulted from the comparison between MDS and normal CD34-positive cell populations. Our results suggest that in myelodysplastic as well as in normal BM the apoptotic phenomenon predominantly involves the maturing cells. The increase in apoptotic levels which can be observed in myelodysplastic compared to normal BM seems to be mainly due to an increase in apoptosis in the differentiated cell population.

Keywords:
Apoptosis, CD34 antigen, Myelodysplastic syndromes, Stem cell
1.
Greenberg PL: The myelodysplastic syndromes; in Hoffman R, Benz E, Shattil S, Furie B, Cohen H (ed): Hematology: Basic Principles and Practice. New York, Churchill Livingstone, 1994, pp 1098–1121.
2.
Koeffler HP: Myelodysplastic syndromes. Semin Hematol 1996;33:87–94.
3.
Aul C, Bowen DT, Yoshida Y: Pathogenesis, etiology and epidemiology of myelodysplastic syndromes. Haematologica 1998;83:71–86.
4.
Yoshida Y: Hypothesis: Apoptosis may be the mechanism responsible for the premature intramedullary cell death in the myelodysplastic syndrome. Leukemia 1993;7:144–146.
5.
Greenberg PL: Apoptosis and its role in the myelodysplastic syndromes: Implication for disease natural history and treatment. Leuk Res 1998;22:1123–1136.
6.
Parker JE, Mufti GJ: Ineffective haemopoiesis and apoptosis in myelodysplastic syndromes. Br J Haematol 1998;101:220–230.
7.
Yoshida Y, Mufti GJ: Apoptosis and its significance in MDS: Controversies revisited. Leuk Res 1999;23:777–785.
8.
Rajapaksa R, Ginzton N, Lusijah SR, Greenberg PL: Altered oncoprotein expression and apoptosis in myelodysplastic syndrome marrow cells. Blood 1996;88:4275–4287.
9.
Bouscary D, De Vos J, Guesnu M, Jondeau K, Viguier F, Melle J, Picard F, Dreyfus F, Fontenay-Roupie M: Fas/Apo-1(CD95) expression and apoptosis in patients with myelodysplastic syndromes. Leukemia 1997;11:839–845.
10.
Kitagawa M, Yamaguchi S, Takahashi M, Tanizawa T, Hirokawa K, Kamiyama R: Localization of Fas and Fas ligand in bone marrow cells demonstrating myelodysplasia. Leukemia 1998;12:486–492.
11.
Parker JE, Fishlock KL, Mijovic A, Czepulkowski B, Pagliuca A, Mufti GJ: ‘Low-risk’ myelodysplastic syndrome is associated with excessive apoptosis and an increased ratio of pro- versus anti-apoptotic bcl-2-related proteins. Br J Haematol 1998;103:1075–1082.
12.
Mundle S, Venugopal P, Shetty V, Ali A, Chopra H, Handa H, Rose S, Mativi BY, Gregory SA, Preisler HD, Raza A: The relative extent and propensity of CD34+ vs. CD34– cells to undergo apoptosis in myelodysplastic marrows. Int J Hematol 1999;69:152–159.
13.
Tsoplou P, Kouraklis-Symeonidis A, Thanopoulou E, Zikos P, Orphanos V, Zoumbos NC: Apoptosis in patients with myelodysplastic syndromes: Differential involvement of marrow cells in ‘good’ versus ‘poor’ prognosis patients and correlation with apoptosis-related genes. Leukemia 1999;13:1554–1563.
14.
Matthes TW, Meyer G, Samii K, Beris P: Increased apoptosis in acquired sideroblastic anemia. Br J Haematol 2000;111:843–852.
15.
Parker JE, Mufti GJ, Rasool F, Mijovic A, Devereux S, Pagliuca A: The role of apoptosis, proliferation and the Bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS. Blood 2000;96:3932–3938.
16.
Novitzky N, Mohamed R, Finlayson J, du Toit C: Increased apoptosis of bone marrow cells and preserved proliferative capacity of selected progenitors predict for clinical response to anti-inflammatory therapy in myelodysplastic syndromes. Exp Hematol 2000;28:941–949.
17.
Hellstrom-Lindberg E, Schmidt-Mende J, Forsblom AM, Christensson B, Fadeel B, Zhivotovsky B: Apoptosis in refractory anaemia with ringed sideroblasts is initiated at the stem cell level and associated with increased activation of caspases. Br J Haematol 2001;112:714–726.
18.
Berger G, Hunault-Berger M, Rachieru P, Fontenay-Roupie M, Baranger L, Ifrah N, Zandecki M: Increased apoptosis in mononucleated cells but not in CD34+ cells in blastic forms of myelodysplastic syndromes. Hematol J 2001;2:87–96.
19.
Raza A, Gezer S, Mundle S, Gao X, Alvi S, Borok R, Rifkin S, Iftikhar A, Shetty V, Parcharidou A, Loew J, Marcus B, Khan Z, Chaney C, Showel J, Gregory S, Preisler H: Apoptosis in bone marrow biopsy samples involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes. Blood 1995;86:268–276.
20.
Tsouplou P, Zoumbos N: Programmed cell death (PCD) in the marrow of patients with myelodysplastic and myeloproliferative diseases concerns almost exclusively CD34+ cells. Blood 1996;88(suppl 1):95a.
21.
Ricciardi MR, Petrucci MT, Ariola C, Gregorj C, Mazzola R, Latagliata R, Petti MC, Tafuri A: High levels of apoptosis characterize RAEB and are lost during leukemic transformation. Blood 1997;90(suppl 1):520a.
22.
Invernizzi R, Pecci A, Bellotti L, Ascari E: Expression of p53, bcl-2 and ras oncoproteins and apoptosis levels in acute leukemias and myelodysplastic syndromes. Leuk Lymphoma 2001;42:481–489.
23.
Lepelley P, Campergue L, Grardel N, Preudhomme C, Cosson A, Fenaux P: Is apoptosis a massive process in myelodysplastic syndromes? Br J Haematol 1996;95:368–371.
24.
Kroemer G, Petit P, Zamzami N, Vayssiere JL, Mignotte B: The biochemistry of programmed cell death. FASEB J 1995;9:1277–1287.
25.
Shetty V, Hussaini S, Broady-Robinson L, Allampallam K, Mundle S, Borok R, Broderick E, Mazzoran L, Zorat F, Raza A: Intramedullary apoptosis of hematopoietic cells in myelodysplastic syndrome patients can be massive: Apoptotic cells recovered from high-density fraction of bone marrow aspirates. Blood 2000;96:1388–1392.
© 2003 S. Karger AG, Basel
2002
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.