Abstract
Three consecutive polycythemia vera (PV) patients were analyzed before and during pegylated-interferon (rIFNα) treatment for the following markers: (1) granulocyte and CD34+ cell clonality, (2) Jak2V617F expression, (3) PRV-1 mRNA overexpression, and (4) Epo-independent colony (EEC) growth. Before rIFNα therapy, all patients displayed clonal hematopoiesis, 100% Jak2V617F expression as well as PRV-1 overexpression, and EEC growth. After rIFNα treatment, all three patients demonstrated polyclonal hematopoiesis. Nonetheless, Jak2V617F expression, PRV-1 overexpression, and EEC-growth remained detectable, albeit at lower levels. We conclude that reemergence of polyclonal hematopoiesis after rIFNα treatment may be achieved in a substantial proportion of patients. However, this does not constitute elimination of the PV clone. These data demonstrate the usefulness of novel markers in monitoring minimal residual disease and caution against discontinuation of rIFNα treatment after hematologic remission. Long-term follow-up of large patient cohorts is required to determine whether rIFNα treatment can cause complete molecular remissions in PV.
Similar content being viewed by others
References
Barbui T (2004) The leukemia controversy in myeloproliferative disorders: is it a natural progression of disease, a secondary sequela of therapy, or a combination of both? Semin Hematol 41:15–17
Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, Vassiliou GS, Bench AJ, Boyd EM, Curtin N, Scott MA, Erber WN, Green AR (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365:1054–1061
Cortes J, O’Brien S, Kantarjian H (2004) Discontinuation of imatinib therapy after achieving a molecular response. Blood 104:2204–2205
Fruchtman SM (2004) Treatment paradigms in the management of myeloproliferative disorders. Semin Hematol 41:18–22
Fruehauf S, Topaly J, Villalobos M, Veldwijk MR, Laufs S, Ho AD (2003) Quantitative real-time polymerase chain reaction shows that treatment with interferon reduces the initially upregulated PRV-1 expression in polycythemia vera patients. Haematologica 88:349–351
Green AR, Vassiliou GS, Curtin N, Campbell PJ (2004) Management of the myeloproliferative disorders : distinguishing data from dogma. Hematol J 5:S126–S132
Griesshammer M, Klippel S, Strunck E, Temerinac S, Mohr U, Heimpel H, Pahl HL (2004) PRV-1 mRNA expression discriminates two types of essential thrombocythemia. Ann Hematol 83:364–370
Hino M, Futami E, Okuno S, Miki T, Nishizawa Y, Morii H (1993) Possible selective effects of interferon alpha-2b on a malignant clone in a case of polycythemia vera. Ann Hematol 66:161–162
James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, Garcon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W (2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 27:27
Johansson P, Ricksten A, Wasslavik C, Johansson B, Andreasson B (2004) The effects of hydroxyurea on PRV-1 expression in patients with essential thrombocythemia and polycythemia vera. Haematologica 89:1264–1266
Klippel S, Strunck E, Temerinac S, Bench AJ, Meinhardt G, Mohr U, Leichtle R, Green AR, Griesshammer M, Heimpel H, Pahl HL (2003) Quantification of PRV-1 mRNA distinguishes polycythemia vera from secondary erythrocytosis. Blood 102:3569–3574
Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, Tichelli A, Cazzola M, Skoda RC (2005) A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 352:1779–1790
Lehmann U, Hasemeier B, Lilischkis R, Kreipe H (2001) Quantitative analysis of promoter hypermethylation in laser-microdissected archival specimens. Lab Invest 81:635–638
Levine R, Wadleigh M, Cools J, Ebert B, Wernig G, Huntley B, Boggon T, Wlodarska I, Clark J, Moore S, Adelsperger J, Koo S, Lee J, Gabriel G, Mercher T, D’Andrea A, Fröhling S, Döhner K, Marynen P, Vandenberghe P, Mesa R, Tefferi A, Griffin J, Eck M, Sellers W, Meyerson M, Golub T, Lee S, Gilliland D (2005) Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7:387–397
Liu E, Jelinek J, Pastore YD, Guan YL, Prchal JF, Prchal JT (2003) Discrimination of polycythemias and thrombocytoses by novel, simple, accurate clonality assays and comparison with PRV-1 expression and BFU-E response to erythropoietin. Blood 101:3294–3301
Massaro P, Foa P, Pomati M, LaTargia ML, Iurlo A, Clerici C, Caldiera S, Fornier M, Maiolo AT (1997) Polycythemia vera treated with recombinant interferon-alpha 2a: evidence of a selective effect on the malignant clone. Am J Hematol 56:126–128
Mauro MJ, Druker BJ, Maziarz RT (2004) Divergent clinical outcome in two CML patients who discontinued imatinib therapy after achieving a molecular remission. Leuk Res 28:S71–S73
Messora C, Bensi L, Vecchi A, Longo R, Giacobbi F, Temperani P, Bevini M, Emilia G, Sacchi S (1994) Cytogenetic conversion in a case of polycythaemia vera treated with interferon-alpha. Br J Haematol 86:402–404
Sacchi S, Leoni P, Liberati M, Riccardi A, Tabilio A, Tartoni P, Messora C, Vecchi A, Bensi L, Rupoli S et al (1994) A prospective comparison between treatment with phlebotomy alone and with interferon-alpha in patients with polycythemia vera. Ann Hematol 68:247–50
Silver RT (1997) Interferon alfa: effects of long-term treatment for polycythemia vera. Semin Hematol 34:40–50
Silver RT (2005) Treatment of polycythemia vera with recombinant interferon alpha (rIFNalpha) or imatinib mesylate. Curr Hematol Rep 4:235–237
Spivak JL (2002) Polycythemia vera: myths, mechanisms, and management (Review). Blood 100:4272–4290
Tefferi A (2003) A contemporary approach to the diagnosis and management of polycythemia vera. Curr Hematol Rep 2:237–241
Temerinac S, Klippel S, Strunck E, Röder S, Lübbert M, Lange W, Azemar M, Meinhardt G, Schaefer HE, Pahl HL (2000) Cloning of PRV-1, a novel member of the uPAR receptor superfamily, which is overexpressed in polycythemia rubra vera. Blood 95:2569–2576
Uchida T, Ohashi H, Aoki E, Nakahara Y, Hotta T, Murate T, Saito H, Kinoshita T (2000) Clonality analysis by methylation-specific PCR for the human androgen-receptor gene (HUMARA-MSP). Leukemia 14:207–212
Acknowledgements
The authors would like to thank Dr. R. Silver for the insightful and critical revision of the manuscript, Britta Hasemeier for the excellent technical assistance Dr. G. Hagner for the help in sample collection, and Prof. Dr. K. Geiger for his continuing support. This work was supported by grants from the Else-Kröner-Fresenius-Stiftung as well as the Alfried-Krupp-Förderpreis to H. L. P.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Steimle, C., Lehmann, U., Temerinac, S. et al. Biomarker analysis in polycythemia vera under interferon-alpha treatment: clonality, EEC, PRV-1, and JAK2 V617F. Ann Hematol 86, 239–244 (2007). https://doi.org/10.1007/s00277-006-0214-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-006-0214-1