FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 338:564-571 February 26, 1998 Number 9 Next

	Full Text PDF Editorial by Schwartz, R. S. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Deregulating the expression of Bcl-x_L, an inhibitor of apoptosis, in an erythropoietin-dependent erythroblast cell line averts apoptosis induced by the withdrawal of erythropoietin. Since in polycythemia vera an abnormal clone of erythroid progenitors is independent of erythropoietin, we investigated whether the endogenous expression of Bcl-x_L was deregulated in these cells.

Methods Erythroid colonies from patients with polycythemia vera and normal subjects were cultured in the presence and absence of erythropoietin and assessed by immunocytochemical and flow-cytometric analysis with anti–Bcl-x antibodies that recognize the two species of Bcl-x (Bcl-x _L and Bcl-x_S). Reverse-transcriptase–polymerase-chain-reaction analysis was used to determine which one of the two species was responsible for anti–Bcl-x staining. Bone marrow mononuclear cells from 8 healthy bone marrow donors, 14 patients with polycythemia vera, 19 patients with other myeloproliferative syndromes, and 12 patients with secondary erythrocytosis were analyzed by flow cytometry with antibodies against Bcl-x and glycophorin A, an erythroid marker.

Results Erythroid cells from patients with polycythemia vera survived in vitro without erythropoietin, and this finding correlated with the expression of Bcl-x protein (Bcl-x_L messenger RNA was the main species of Bcl-x found), even in mature erythroblasts that normally do not express Bcl-x. The mean (±SD) percentage of cells positive for both glycophorin A and Bcl-x in the 14 patients with polycythemia vera (21.8±3.6 percent) was significantly higher than that in 8 normal donors (6.62±1.58 percent), 12 patients with secondary erythrocytosis (6.87±1.95 percent), 9 patients with essential thrombocythemia (3.81±0.97 percent), and 10 patients with chronic myeloid leukemia (2.7±0.41 percent).

Conclusions Deregulated expression of Bcl-x may contribute to the erythropoietin-independent survival of erythroid-lineage cells in polycythemia vera and thereby contribute to the pathogenesis of this disease.

Source Information

From the Servicio de Immunologia (M.S., A.B., C.S., J.L.F.-L.) and Servicio de Hematologia (C.R., I.O.), Hospital Universitario Marqués de Valdecilla, Santander, Spain.

Address reprint requests to Dr. Fernández-Luna at the Servicio de Immunologia, Hospital Universitario Marqués de Valdecilla, INSALUD, 39008 Santander, Spain.

Full Text of this Article

This article has been cited by other articles:

• Hexner, E. O., Serdikoff, C., Jan, M., Swider, C. R., Robinson, C., Yang, S., Angeles, T., Emerson, S. G., Carroll, M., Ruggeri, B., Dobrzanski, P. (2008). Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood 111: 5663-5671 [Abstract] [Full Text]  
• Ciurea, S. O., Merchant, D., Mahmud, N., Ishii, T., Zhao, Y., Hu, W., Bruno, E., Barosi, G., Xu, M., Hoffman, R. (2007). Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis. Blood 110: 986-993 [Abstract] [Full Text]  
• Teofili, L., Martini, M., Cenci, T., Petrucci, G., Torti, L., Storti, S., Guidi, F., Leone, G., Larocca, L. M. (2007). Different STAT-3 and STAT-5 phosphorylation discriminates among Ph-negative chronic myeloproliferative diseases and is independent of the V617F JAK-2 mutation. Blood 110: 354-359 [Abstract] [Full Text]  
• Diwan, A., Koesters, A. G., Odley, A. M., Pushkaran, S., Baines, C. P., Spike, B. T., Daria, D., Jegga, A. G., Geiger, H., Aronow, B. J., Molkentin, J. D., Macleod, K. F., Kalfa, T. A., Dorn, G. W. II (2007). Unrestrained erythroblast development in Nix-/- mice reveals a mechanism for apoptotic modulation of erythropoiesis. Proc. Natl. Acad. Sci. USA 104: 6794-6799 [Abstract] [Full Text]  
• Campbell, P. J., Green, A. R. (2006). The Myeloproliferative Disorders. NEJM 355: 2452-2466 [Full Text]  
• Garcon, L., Rivat, C., James, C., Lacout, C., Camara-Clayette, V., Ugo, V., Lecluse, Y., Bennaceur-Griscelli, A., Vainchenker, W. (2006). Constitutive activation of STAT5 and Bcl-xL overexpression can induce endogenous erythroid colony formation in human primary cells. Blood 108: 1551-1554 [Abstract] [Full Text]  
• Bellanne-Chantelot, C., Chaumarel, I., Labopin, M., Bellanger, F., Barbu, V., De Toma, C., Delhommeau, F., Casadevall, N., Vainchenker, W., Thomas, G., Najman, A. (2006). Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders. Blood 108: 346-352 [Abstract] [Full Text]  
• Schafer, A. I. (2006). Molecular basis of the diagnosis and treatment of polycythemia vera and essential thrombocythemia. Blood 107: 4214-4222 [Abstract] [Full Text]  
• Zeuner, A., Pedini, F., Signore, M., Ruscio, G., Messina, C., Tafuri, A., Girelli, G., Peschle, C., De Maria, R. (2006). Increased death receptor resistance and FLIPshort expression in polycythemia vera erythroid precursor cells. Blood 107: 3495-3502 [Abstract] [Full Text]  
• Levine, R. L., Wernig, G. (2006). Role of JAK-STAT Signaling in the Pathogenesis of Myeloproliferative Disorders. ASH Education Book 2006: 233-239 [Abstract] [Full Text]  
• Jones, A. V., Kreil, S., Zoi, K., Waghorn, K., Curtis, C., Zhang, L., Score, J., Seear, R., Chase, A. J., Grand, F. H., White, H., Zoi, C., Loukopoulos, D., Terpos, E., Vervessou, E.-C., Schultheis, B., Emig, M., Ernst, T., Lengfelder, E., Hehlmann, R., Hochhaus, A., Oscier, D., Silver, R. T., Reiter, A., Cross, N. C. P. (2005). Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 106: 2162-2168 [Abstract] [Full Text]  
• STEIDL, U., SCHROEDER, T., STEIDL, C., KOBBE, G., GRAEF, T., BORK, S., PECHTEL, S., KLISZEWSKI, S., KUENDGEN, A., ROHR, U. P., FENK, R., SCHROEDER, M., HAASE, D., HAAS, R., KRONENWETT, R. (2005). Distinct Gene Expression Pattern of Malignant Hematopoietic Stem and Progenitor Cells in Polycythemia Vera. Ann. N. Y. Acad. Sci. 1044: 94-108 [Abstract] [Full Text]  
• Kaushansky, K. (2005). On the molecular origins of the chronic myeloproliferative disorders: it all makes sense. Blood 105: 4187-4190 [Full Text]  
• Vainchenker, W., Constantinescu, S. N. (2005). A Unique Activating Mutation in JAK2 (V617F) Is at the Origin of Polycythemia Vera and Allows a New Classification of Myeloproliferative Diseases. ASH Education Book 2005: 195-200 [Abstract] [Full Text]  
• Campbell, P. J., Green, A. R. (2005). Management of Polycythemia Vera and Essential Thrombocythemia. ASH Education Book 2005: 201-208 [Abstract] [Full Text]  
• Kaushansky, K. (2005). On the Molecular Origins of the Chronic Myeloproliferative Disorders: It All Makes Sense. ASH Education Book 2005: 533-537 [Full Text]  
• Tenedini, E., Fagioli, M. E., Vianelli, N., Tazzari, P. L., Ricci, F., Tagliafico, E., Ricci, P., Gugliotta, L., Martinelli, G., Tura, S., Baccarani, M., Ferrari, S., Catani, L. (2004). Gene expression profiling of normal and malignant CD34-derived megakaryocytic cells. Blood 104: 3126-3135 [Abstract] [Full Text]  
• Carlsson, G., Aprikyan, A. A. G., Tehranchi, R., Dale, D. C., Porwit, A., Hellstrom-Lindberg, E., Palmblad, J., Henter, J.-I., Fadeel, B. (2004). Kostmann syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, constitutive mitochondrial release of cytochrome c, and excessive apoptosis of myeloid progenitor cells. Blood 103: 3355-3361 [Abstract] [Full Text]  
• Xu, M.-j., Sui, X., Zhao, R., Dai, C., Krantz, S. B., Zhao, Z. J. (2003). PTP-MEG2 is activated in polycythemia vera erythroid progenitor cells and is required for growth and expansion of erythroid cells. Blood 102: 4354-4360 [Abstract] [Full Text]  
• Acosta, J. C., Richard, C., Delgado, M. D., Horita, M., Rizzo, M. G., Fernandez-Luna, J. L., Leon, J. (2003). Amifostine impairs p53-mediated apoptosis of human myeloid leukemia cells. Molecular Cancer Therapeutics 2: 893-900 [Abstract] [Full Text]  
• Pellagatti, A., Vetrie, D., Langford, C. F., Gama, S., Eagleton, H., Wainscoat, J. S., Boultwood, J. (2003). Gene Expression Profiling in Polycythemia Vera Using cDNA Microarray Technology. Cancer Res. 63: 3940-3944 [Abstract] [Full Text]  
• Aerbajinai, W., Giattina, M., Lee, Y. T., Raffeld, M., Miller, J. L. (2003). The proapoptotic factor Nix is coexpressed with Bcl-xL during terminal erythroid differentiation. Blood 102: 712-717 [Abstract] [Full Text]  
• Gray, H. E., Weigand, C. M., Cottrill, N. B., Willis, A. M., Morgan, R. V. (2003). Polycythemia Vera in a Dog Presenting With Uveitis. Journal of the American Animal Hospital Association 39: 355-360 [Abstract] [Full Text]  
• Spivak, J. L. (2002). Polycythemia vera: myths, mechanisms, and management. Blood 100: 4272-4290 [Full Text]  
• Giraudier, S., Chagraoui, H., Komura, E., Barnache, S., Blanchet, B., LeCouedic, J. P., Smith, D. F., Larbret, F., Taksin, A.-L., Moreau-Gachelin, F., Casadevall, N., Tulliez, M., Hulin, A., Debili, N., Vainchenker, W. (2002). Overexpression of FKBP51 in idiopathic myelofibrosis regulates the growth factor independence of megakaryocyte progenitors. Blood 100: 2932-2940 [Abstract] [Full Text]  
• Itoh, J, de la Motte, C, Strong, S A, Levine, A D, Fiocchi, C (2001). Decreased Bax expression by mucosal T cells favours resistance to apoptosis in Crohn's disease. Gut 49: 35-41 [Abstract] [Full Text]  
• Dai, C., Krantz, S. B. (2001). Increased expression of the INK4a/ARF locus in polycythemia vera. Blood 97: 3424-3432 [Abstract] [Full Text]  
• Weinstein, R. S., Nicholas, R. W., Manolagas, S. C. (2000). Apoptosis of Osteocytes in Glucocorticoid-Induced Osteonecrosis of the Hip. J. Clin. Endocrinol. Metab. 85: 2907-2912 [Abstract] [Full Text]  
• Klippel, S., Strunck, E., Roder, S., Lubbert, M., Lange, W., Azemar, M., Meinhardt, G., Schaefer, H.-E., Pahl, H. L. (2000). Cloning of PRV-1, a novel member of the uPAR receptor superfamily, which is overexpressed in polycythemia rubra vera. Blood 95: 2569-2576 [Abstract] [Full Text]  
• Pearson, T. C., Messinezy, M., Westwood, N., Green, A. R., Bench, A. J., Green, A. R., Huntly, B. J.P., Nacheva, E. P., Barbui, T., Finazzi, G. (2000). A Polycythemia Vera Update: Diagnosis, Pathobiology, and Treatment. ASH Education Book 2000: 51-68 [Abstract] [Full Text]  
• Silva, M., Benito, A., Sanz, C., Prosper, F., Ekhterae, D., Nunez, G., Fernandez-Luna, J. L. (1999). Erythropoietin Can Induce the Expression of Bcl-xL through Stat5 in Erythropoietin-dependent Progenitor Cell Lines. J. Biol. Chem. 274: 22165-22169 [Abstract] [Full Text]  
• Packham, G., White, E. L., Eischen, C. M., Yang, H., Parganas, E., Ihle, J. N., Grillot, D. A.M., Zambetti, G. P., Nuñez, G., Cleveland, J. L. (1998). Selective regulation of Bcl-XL by a Jak kinase-dependent pathway is bypassed in murine hematopoietic malignancies. Genes Dev. 12: 2475-2487 [Abstract] [Full Text]  
• Sinkovics, J. G., Horvath, J. C., Savitz, S., Hetts, S. W. (1998). Role of Apoptosis in Health and Disease. JAMA 279: 1699-1700 [Full Text]  
• Schwartz, R. S. (1998). Polycythemia Vera -- Chance, Death, and Mutability. NEJM 338: 613-615 [Full Text]