Skip to main content
Top
Published in: Current Hematologic Malignancy Reports 4/2013

01-12-2013 | Myeloproliferative Disorders (JJ Kiladjian, Section Editor)

Molecular Classification of Myeloproliferative Neoplasms—Pros and Cons

Authors: Moosa Qureshi, Claire Harrison

Published in: Current Hematologic Malignancy Reports | Issue 4/2013

Login to get access

Abstract

Dameshek first postulated a common myeloproliferative heritage for the myeloproliferative disorders, now termed neoplasms. This prescient observation was validated by the description of a common mutation in exon 14 of JAK2 for patients with essential thrombocythemia, polycythemia vera and primary myelofibrosis. In recent years, our knowledge of the molecular abnormalities underpinning these disorders has expanded significantly. At the same time, we have continued to use a classification based largely upon the first clinical descriptions of these entities, which sometimes proves problematic in differentiating between these conditions and normal reactive processes, myelodysplasia and between the myeloproliferative neoplasm entities themselves. Here, we discuss the pros and cons of a molecular classification and its potential utility in diagnosis, prognosis, and therapeutics.
Literature
1.
go back to reference Tefferi A. The history of myeloproliferative disorders: before and after Dameshek. Leukemia. 2008;22(1):3–13.PubMedCrossRef Tefferi A. The history of myeloproliferative disorders: before and after Dameshek. Leukemia. 2008;22(1):3–13.PubMedCrossRef
2.
go back to reference Dameshek W. Some speculations on the myeloproliferative syndromes. Blood. 1951;6:372–5.PubMed Dameshek W. Some speculations on the myeloproliferative syndromes. Blood. 1951;6:372–5.PubMed
3.
4.
go back to reference Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer. 2009;115(17):3842–7.PubMedCrossRef Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. Cancer. 2009;115(17):3842–7.PubMedCrossRef
5.
go back to reference Beer PA, Erber WN, Campbell PJ, Green AR. How I treat essential thrombocythemia. Blood. 2011;117(5):1472–82.PubMedCrossRef Beer PA, Erber WN, Campbell PJ, Green AR. How I treat essential thrombocythemia. Blood. 2011;117(5):1472–82.PubMedCrossRef
6.
go back to reference Laubach JP, Fu P, Jiang X, Salter KH, Potti A, Arcasoy MO. Polycythemia vera erythroid precursors exhibit increased proliferation and apoptosis resistance associated with abnormal RAS and PI3K pathway activation. Exp Hematol. 2009;37(12):1411–22.PubMedCrossRef Laubach JP, Fu P, Jiang X, Salter KH, Potti A, Arcasoy MO. Polycythemia vera erythroid precursors exhibit increased proliferation and apoptosis resistance associated with abnormal RAS and PI3K pathway activation. Exp Hematol. 2009;37(12):1411–22.PubMedCrossRef
7.
go back to reference Bersenev A, Wu C, Balcerek J, Jing J, Kundu M, Blobel GA, et al. Lnk constrains myeloproliferative diseases in mice. J Clin Invest. 2010;120(6):2058–69.PubMedCrossRef Bersenev A, Wu C, Balcerek J, Jing J, Kundu M, Blobel GA, et al. Lnk constrains myeloproliferative diseases in mice. J Clin Invest. 2010;120(6):2058–69.PubMedCrossRef
8.
go back to reference Suzuki N, Yamazaki S, Ema H, Yamaguchi T, Nakauchi H, Takaki S. Homeostasis of hematopoietic stem cells regulated by the myeloproliferative disease associated-gene product Lnk/Sh2b3 via Bcl-xL. Exp Hematol. 2012;40(2):166–74.PubMedCrossRef Suzuki N, Yamazaki S, Ema H, Yamaguchi T, Nakauchi H, Takaki S. Homeostasis of hematopoietic stem cells regulated by the myeloproliferative disease associated-gene product Lnk/Sh2b3 via Bcl-xL. Exp Hematol. 2012;40(2):166–74.PubMedCrossRef
9.
go back to reference Seeger T, Schanne D, Pahl H. Expression of the transcription factor NF-E2 is regulated via the novel epigenetic JAK2/H3Y41PH/HP1A pathway [abstract]. Haematol EHA Abstr Book. 2013;98(s1):106. Seeger T, Schanne D, Pahl H. Expression of the transcription factor NF-E2 is regulated via the novel epigenetic JAK2/H3Y41PH/HP1A pathway [abstract]. Haematol EHA Abstr Book. 2013;98(s1):106.
10.
go back to reference Peeken J, Wehrle J, Gothwal M, Seeger T, Pahl H. Characterization of JMJD1C and JMJD2C as novel NF-E2 target genes [abstract]. Haematol EHA Abstr Book. 2013;98(s1):106. Peeken J, Wehrle J, Gothwal M, Seeger T, Pahl H. Characterization of JMJD1C and JMJD2C as novel NF-E2 target genes [abstract]. Haematol EHA Abstr Book. 2013;98(s1):106.
11.
go back to reference • Weigert O, Lane AA, Bird L, Kopp N, Chapuy B, van Bodegom D, et al. Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition. J Exp Med. 2012;209(2)):259–73. First descriptions of mechanisms of JAK 2 inhibitor resistance in vitro and mechanisms to potentially overcome them.PubMedCrossRef • Weigert O, Lane AA, Bird L, Kopp N, Chapuy B, van Bodegom D, et al. Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition. J Exp Med. 2012;209(2)):259–73. First descriptions of mechanisms of JAK 2 inhibitor resistance in vitro and mechanisms to potentially overcome them.PubMedCrossRef
12.
go back to reference • Koppikar P, Bhagwat N, Kilpivaara O, Manshouri T, Adli M, Hricik T, et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature. 2012;489:155–9. First descriptions of mechanisms of JAK 2 inhibitor resistance in vitro and mechanisms to potentially overcome them.PubMedCrossRef • Koppikar P, Bhagwat N, Kilpivaara O, Manshouri T, Adli M, Hricik T, et al. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature. 2012;489:155–9. First descriptions of mechanisms of JAK 2 inhibitor resistance in vitro and mechanisms to potentially overcome them.PubMedCrossRef
13.
go back to reference Akada H, Akada S, Yan D, Hutchison R, Mohi G. Loss of wild-type Jak2 allele enhances myeloid cell expansion and accelerates myelofibrosis in Jak2V617F knock-in mice [abstract]. ASH Annu Meet Abstra. 2012;120:809. Akada H, Akada S, Yan D, Hutchison R, Mohi G. Loss of wild-type Jak2 allele enhances myeloid cell expansion and accelerates myelofibrosis in Jak2V617F knock-in mice [abstract]. ASH Annu Meet Abstra. 2012;120:809.
14.
go back to reference Tiedt R, Hao-Shen H, Sobas MA, Looser R, Dirnhofer S, Schwaller J, et al. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood. 2008;111(8):3931–40.PubMedCrossRef Tiedt R, Hao-Shen H, Sobas MA, Looser R, Dirnhofer S, Schwaller J, et al. Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood. 2008;111(8):3931–40.PubMedCrossRef
15.
go back to reference Vannucchi AM, Antonioli E, Guglielmelli P, Pardanani A, Tefferi A. Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: a critical reappraisal. Leukemia. 2008;22:1299–307.PubMedCrossRef Vannucchi AM, Antonioli E, Guglielmelli P, Pardanani A, Tefferi A. Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: a critical reappraisal. Leukemia. 2008;22:1299–307.PubMedCrossRef
16.
go back to reference • Godfrey AL, Chen E, Pagano F, Ortmann CA, Silber Y, Bellosillo B, et al. JAK2V617F homozygosity arises commonly and recurrently in PV and ET, but PV is characterized by expansion of a dominant homozygous subclone. Blood. 2012;120(13):2704–7. Insight into clonal expansion in MPN and its role in disease phenotype.PubMedCrossRef • Godfrey AL, Chen E, Pagano F, Ortmann CA, Silber Y, Bellosillo B, et al. JAK2V617F homozygosity arises commonly and recurrently in PV and ET, but PV is characterized by expansion of a dominant homozygous subclone. Blood. 2012;120(13):2704–7. Insight into clonal expansion in MPN and its role in disease phenotype.PubMedCrossRef
17.
go back to reference Saliba J, Hamidi S, Stefano AD, Langlois T, Lenglet G, Secardin L, et al. Modeling JAK2V617F heterozygous and homozygous mutations by using induced pluripotent stem cells derived from myeloproliferative neoplasms patients [abstract]. ASH Annu Meet Abstra. 2012;120:1758. Saliba J, Hamidi S, Stefano AD, Langlois T, Lenglet G, Secardin L, et al. Modeling JAK2V617F heterozygous and homozygous mutations by using induced pluripotent stem cells derived from myeloproliferative neoplasms patients [abstract]. ASH Annu Meet Abstra. 2012;120:1758.
18.
go back to reference Godfrey AL, Chen E, Pagano F, Silber Y, Campbell PJ, Green AR. Clonal analyses reveal associations of JAK2V617F homozygosity with hematologic features, age and gender in polycythemia vera and essential thrombocythemia. Haematologica. 2013;98:718–21.PubMedCrossRef Godfrey AL, Chen E, Pagano F, Silber Y, Campbell PJ, Green AR. Clonal analyses reveal associations of JAK2V617F homozygosity with hematologic features, age and gender in polycythemia vera and essential thrombocythemia. Haematologica. 2013;98:718–21.PubMedCrossRef
19.
go back to reference Huang L, Yao H, Ma Y. JAK2 signaling specifies phenotypic pleiotropy in myeloproliferative neoplasms [abstract]. ASH Annu Meet Abstra. 2012;120:2868. Huang L, Yao H, Ma Y. JAK2 signaling specifies phenotypic pleiotropy in myeloproliferative neoplasms [abstract]. ASH Annu Meet Abstra. 2012;120:2868.
20.
21.
go back to reference Pérez C, Pascual M, Martin-Subero JI, Bellosillo B, Segura V, Delabesse E et al. Aberrant DNA methylation profile of chronic and transformed classic philadelphia-negative myeloproliferative neoplasms. Haematologica 2013 May 28 [Epub ahead of print]. Pérez C, Pascual M, Martin-Subero JI, Bellosillo B, Segura V, Delabesse E et al. Aberrant DNA methylation profile of chronic and transformed classic philadelphia-negative myeloproliferative neoplasms. Haematologica 2013 May 28 [Epub ahead of print].
22.
go back to reference • Nischal S, Bhattacharyya S, Christopeit M, Yu Y, Zhou L, Bhagat TD, et al. Methylome profiling reveals distinct alterations in phenotypic and mutational subgroups of myeloproliferative neoplasms. Cancer Res. 2013;73(3):1076–85. Data regarding methylation and modification of DNA in the different subtypes of MPN.PubMedCrossRef • Nischal S, Bhattacharyya S, Christopeit M, Yu Y, Zhou L, Bhagat TD, et al. Methylome profiling reveals distinct alterations in phenotypic and mutational subgroups of myeloproliferative neoplasms. Cancer Res. 2013;73(3):1076–85. Data regarding methylation and modification of DNA in the different subtypes of MPN.PubMedCrossRef
23.
go back to reference Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell. 2011;20(1):11–24.PubMedCrossRef Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C, et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell. 2011;20(1):11–24.PubMedCrossRef
24.
go back to reference • Zhan H, Cardozo C, Raza A. MicroRNAs in myeloproliferative neoplasms. BJH. 2013;161:471–83. A useful review of micro RNA and discussion of data regarding their potential role in MPN.PubMedCrossRef • Zhan H, Cardozo C, Raza A. MicroRNAs in myeloproliferative neoplasms. BJH. 2013;161:471–83. A useful review of micro RNA and discussion of data regarding their potential role in MPN.PubMedCrossRef
25.
go back to reference • Zhan H, Cardozo C, Yu W, Wang A, Moliterno AR, Dang CV, et al. MicroRNA deregulation in polycythemia vera and essential thrombocythemia patients. Blood Cells Mol Dis. 2012;50:190–5. A useful review of micro RNA and discussion of data regarding their potential role in MPN.PubMedCrossRef • Zhan H, Cardozo C, Yu W, Wang A, Moliterno AR, Dang CV, et al. MicroRNA deregulation in polycythemia vera and essential thrombocythemia patients. Blood Cells Mol Dis. 2012;50:190–5. A useful review of micro RNA and discussion of data regarding their potential role in MPN.PubMedCrossRef
26.
go back to reference Hinds DA, Barnholt KE, Zehnder JL, Kiefer AK, Do CB, Eriksson N, et al. A germline variant in the TERT gene is a novel predisposition allele associated with myeloproliferative neoplasms [abstract]. ASH Annu Meet Abstra. 2012;120:707. Hinds DA, Barnholt KE, Zehnder JL, Kiefer AK, Do CB, Eriksson N, et al. A germline variant in the TERT gene is a novel predisposition allele associated with myeloproliferative neoplasms [abstract]. ASH Annu Meet Abstra. 2012;120:707.
27.
go back to reference Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29(4):392–7.PubMedCrossRef Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29(4):392–7.PubMedCrossRef
28.
go back to reference Vannucchi AM, Antonioli E, Guglielmelli P, Rambaldi A, Barosi G, Marchioli R, et al. Clinical profile of homozygous JAK2 617V> F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007;110(3):840–6.PubMedCrossRef Vannucchi AM, Antonioli E, Guglielmelli P, Rambaldi A, Barosi G, Marchioli R, et al. Clinical profile of homozygous JAK2 617V> F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007;110(3):840–6.PubMedCrossRef
29.
go back to reference Barosi G, Poletto V, Massa M, Campanelli R, Villani L, Bonetti E, et al. JAK2 V617F genotype is a strong determinant of blast transformation in primary myelofibrosis. PLoS One. 2013;8(3):e59791.PubMedCrossRef Barosi G, Poletto V, Massa M, Campanelli R, Villani L, Bonetti E, et al. JAK2 V617F genotype is a strong determinant of blast transformation in primary myelofibrosis. PLoS One. 2013;8(3):e59791.PubMedCrossRef
30.
go back to reference •• Vannucchi AM, Lasho TL, Guglielmelli P, Biamonte F, Pardanani A, Pereira A et al. Mutations and prognosis in primary myelofibrosis. Leukemia 2013 Apr 26 [Epub ahead of print]. Novel and strong data supporting the incorporation of molecular data into clinical risk profile and perhaps then into classification. •• Vannucchi AM, Lasho TL, Guglielmelli P, Biamonte F, Pardanani A, Pereira A et al. Mutations and prognosis in primary myelofibrosis. Leukemia 2013 Apr 26 [Epub ahead of print]. Novel and strong data supporting the incorporation of molecular data into clinical risk profile and perhaps then into classification.
31.
go back to reference •• Lasho TL, Gangat N, Finke C, Laborde RR, Hanson CA, Ketterling RP, et al. Prognostic Interactions Between SRSF2, ASXL1, and IDH Mutations in Primary Myelofibrosis and Determination of Added Value to Cytogenetic Risk Stratification and DIPSS-Plus [abstract]. ASH Annu Meet Abstra. 2012;120:430. Novel and strong data supporting the incorporation of molecular data into clinical risk profile and perhaps then into classification. •• Lasho TL, Gangat N, Finke C, Laborde RR, Hanson CA, Ketterling RP, et al. Prognostic Interactions Between SRSF2, ASXL1, and IDH Mutations in Primary Myelofibrosis and Determination of Added Value to Cytogenetic Risk Stratification and DIPSS-Plus [abstract]. ASH Annu Meet Abstra. 2012;120:430. Novel and strong data supporting the incorporation of molecular data into clinical risk profile and perhaps then into classification.
32.
go back to reference Moliterno AR, Williams DM, McDevitt MA, Stein BL, Gerber JM, Rogers O, et al. Polycythemia Vera: redefinition in the genomic era [abstract]. ASH Annu Meet Abstra. 2012;120:1754. Moliterno AR, Williams DM, McDevitt MA, Stein BL, Gerber JM, Rogers O, et al. Polycythemia Vera: redefinition in the genomic era [abstract]. ASH Annu Meet Abstra. 2012;120:1754.
33.
go back to reference Quintás-Cardama A, Vaddi K, Liu P, Manshouri T, Li J, Scherle PA, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115(15):3109–17.PubMedCrossRef Quintás-Cardama A, Vaddi K, Liu P, Manshouri T, Li J, Scherle PA, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010;115(15):3109–17.PubMedCrossRef
34.
go back to reference •• Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807. JAK inhibitor trials in myelofibrosis.PubMedCrossRef •• Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799–807. JAK inhibitor trials in myelofibrosis.PubMedCrossRef
35.
go back to reference •• Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–98. JAK inhibitor trials in myelofibrosis.PubMedCrossRef •• Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787–98. JAK inhibitor trials in myelofibrosis.PubMedCrossRef
36.
go back to reference Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, Cortes-Franco J, Thomas DA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363(12):1117–27.PubMedCrossRef Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, Cortes-Franco J, Thomas DA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363(12):1117–27.PubMedCrossRef
37.
go back to reference Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. 2011;29(7):789–96.PubMedCrossRef Pardanani A, Gotlib JR, Jamieson C, Cortes JE, Talpaz M, Stone RM, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol. 2011;29(7):789–96.PubMedCrossRef
38.
go back to reference Talpaz M, Jamieson C, Gabrail NY, Lebedinsky C, Gao G, Liu F, et al. A phase II randomized dose-ranging study of the JAK2-selective inhibitor SAR302503 in patients with intermediate-2 or High-Risk Primary Myelofibrosis (MF), Post-Polycythemia Vera (PV) MF, or Post-Essential Thrombocythemia (ET) MF. [abstract]. ASH Annu Meet Abstra. 2012;120:2837. Talpaz M, Jamieson C, Gabrail NY, Lebedinsky C, Gao G, Liu F, et al. A phase II randomized dose-ranging study of the JAK2-selective inhibitor SAR302503 in patients with intermediate-2 or High-Risk Primary Myelofibrosis (MF), Post-Polycythemia Vera (PV) MF, or Post-Essential Thrombocythemia (ET) MF. [abstract]. ASH Annu Meet Abstra. 2012;120:2837.
39.
go back to reference Komrokji R, Wadleigh M, Seymour J, Roberts A, To L, Zhu H, et al. Results of a phase 2 study of pacritinib (SB1518), a novel oral JAK2 inhibitor, in patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis [abstract]. ASH Annu Meet Abstra. 2011;118:282. Komrokji R, Wadleigh M, Seymour J, Roberts A, To L, Zhu H, et al. Results of a phase 2 study of pacritinib (SB1518), a novel oral JAK2 inhibitor, in patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis [abstract]. ASH Annu Meet Abstra. 2011;118:282.
40.
go back to reference Pardanani A, Laborde RR, Lasho TL, Finke C, Begna K, Al-Kali A, et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia. 2013;6:1322–7.CrossRef Pardanani A, Laborde RR, Lasho TL, Finke C, Begna K, Al-Kali A, et al. Safety and efficacy of CYT387, a JAK1 and JAK2 inhibitor, in myelofibrosis. Leukemia. 2013;6:1322–7.CrossRef
41.
go back to reference Deshpande A, Reddy MM, Schade GO, Ray A, Chowdary TK, Griffin JD, et al. Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms. Leukemia. 2012;26(4):708–15.PubMedCrossRef Deshpande A, Reddy MM, Schade GO, Ray A, Chowdary TK, Griffin JD, et al. Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms. Leukemia. 2012;26(4):708–15.PubMedCrossRef
42.
go back to reference Jamal R, Belisle C, Lessard MC, Hebert J, Roy DC, Levine R, et al. Evidence suggesting the presence of a stem cell clone anteceding the acquisition of the JAK2-V617F mutation. Leukemia. 2008;22:1472–4.PubMedCrossRef Jamal R, Belisle C, Lessard MC, Hebert J, Roy DC, Levine R, et al. Evidence suggesting the presence of a stem cell clone anteceding the acquisition of the JAK2-V617F mutation. Leukemia. 2008;22:1472–4.PubMedCrossRef
43.
go back to reference Barrio S, Gallardo M, Arenas A, Ayala R, Rapado I, Rueda D, et al. Inhibition of related JAK/STAT pathways with molecular targeted drugs shows strong synergy with ruxolitinib in chronic myeloproliferative neoplasm. BJH. 2013;161:667–76.PubMedCrossRef Barrio S, Gallardo M, Arenas A, Ayala R, Rapado I, Rueda D, et al. Inhibition of related JAK/STAT pathways with molecular targeted drugs shows strong synergy with ruxolitinib in chronic myeloproliferative neoplasm. BJH. 2013;161:667–76.PubMedCrossRef
44.
go back to reference Walz C, Ahmed W, Lazarides K, Betancur M, Patel N, Hennighausen L, et al. Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2(V617F) in mice. Blood. 2012;119(15):3550–60.PubMedCrossRef Walz C, Ahmed W, Lazarides K, Betancur M, Patel N, Hennighausen L, et al. Essential role for Stat5a/b in myeloproliferative neoplasms induced by BCR-ABL1 and JAK2(V617F) in mice. Blood. 2012;119(15):3550–60.PubMedCrossRef
45.
go back to reference Choong ML, Pecquet C, Tai SJ, Yong JWY, Pendharkar V, Wang S, et al. Combination treatment with JAK2 and PI3K inhibitors in myeloproliferative neoplasms [abstract]. ASH Annu Meet Abstra. 2012;120:180. Choong ML, Pecquet C, Tai SJ, Yong JWY, Pendharkar V, Wang S, et al. Combination treatment with JAK2 and PI3K inhibitors in myeloproliferative neoplasms [abstract]. ASH Annu Meet Abstra. 2012;120:180.
46.
go back to reference Vannucchi AM, Bartalucci N, Bogani C, Martinelli S, Tozzi L, Bosi A, et al. Combined inhibition of JAK2 and mTOR signaling results in enhanced efficacy in in-vitro and preclinical mouse models of JAK2V617F-driven myeloproliferative disease [abstract]. ASH Annu Meet Abstra. 2012;120:708. Vannucchi AM, Bartalucci N, Bogani C, Martinelli S, Tozzi L, Bosi A, et al. Combined inhibition of JAK2 and mTOR signaling results in enhanced efficacy in in-vitro and preclinical mouse models of JAK2V617F-driven myeloproliferative disease [abstract]. ASH Annu Meet Abstra. 2012;120:708.
47.
go back to reference Guglielmelli P, Barosi G, Rambaldi A, Marchioli R, Masciulli A, Tozzi L, et al. Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis. Blood. 2011;118(8):2069–76.PubMedCrossRef Guglielmelli P, Barosi G, Rambaldi A, Marchioli R, Masciulli A, Tozzi L, et al. Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis. Blood. 2011;118(8):2069–76.PubMedCrossRef
48.
go back to reference Bogani C, Bartalucci N, Martinelli S, Tozzi L, Guglielmelli P, Bosi A, et al. mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms. PLoS One. 2013;8(1):e54826.PubMedCrossRef Bogani C, Bartalucci N, Martinelli S, Tozzi L, Guglielmelli P, Bosi A, et al. mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms. PLoS One. 2013;8(1):e54826.PubMedCrossRef
49.
go back to reference Fiskus W, Verstovsek S, Manshouri T, Smith JE, Peth K, Abhyankar S, et al. Dual PI3K/AKT/mTOR inhibitor BEZ235 synergistically enhances the activity of JAK2 inhibitor against cultured and primary human myeloproliferative neoplasm cells. Mol Cancer Ther. 2013;12(5):577–88.PubMedCrossRef Fiskus W, Verstovsek S, Manshouri T, Smith JE, Peth K, Abhyankar S, et al. Dual PI3K/AKT/mTOR inhibitor BEZ235 synergistically enhances the activity of JAK2 inhibitor against cultured and primary human myeloproliferative neoplasm cells. Mol Cancer Ther. 2013;12(5):577–88.PubMedCrossRef
50.
go back to reference Levine RL, Koppikar P, Marubayashi S, Bhagwat N, Taldone T, Park Y, et al. Combination therapy using JAK2 and HSP90 inhibitors increased efficacy in myelofibrosis in vivo [abstract]. ASH Annu Meet Abstra. 2012;120:805. Levine RL, Koppikar P, Marubayashi S, Bhagwat N, Taldone T, Park Y, et al. Combination therapy using JAK2 and HSP90 inhibitors increased efficacy in myelofibrosis in vivo [abstract]. ASH Annu Meet Abstra. 2012;120:805.
51.
go back to reference Wang Y, Fiskus W, Chong DG, Buckley KM, Natarajan K, Rao R, et al. Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells. Blood. 2009;114(24):5024–33.PubMedCrossRef Wang Y, Fiskus W, Chong DG, Buckley KM, Natarajan K, Rao R, et al. Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells. Blood. 2009;114(24):5024–33.PubMedCrossRef
52.
go back to reference Deangelo DJ, Mesa RA, Fiskus W, Tefferi A, Paley C, Wadleigh M, et al. Phase II trial of panobinostat, an oral pan-deacetylase inhibitor in patients with primary myelofibrosis, post-essential thrombocythaemia, and post-polycythaemia vera myelofibrosis. BJH. 2013. doi:10.1111/bjh.12384 [Epub ahead of print].PubMed Deangelo DJ, Mesa RA, Fiskus W, Tefferi A, Paley C, Wadleigh M, et al. Phase II trial of panobinostat, an oral pan-deacetylase inhibitor in patients with primary myelofibrosis, post-essential thrombocythaemia, and post-polycythaemia vera myelofibrosis. BJH. 2013. doi:10.​1111/​bjh.​12384 [Epub ahead of print].PubMed
53.
go back to reference Mascarenhas J, Lu M, Li T, Petersen B, Hochman T, Najfeld V, et al. A phase I study of panobinostat (LBH589) in patients with primary myelofibrosis (PMF) and post-polycythaemia vera/essential thrombocythaemia myelofibrosis (post-PV/ET MF). BJH. 2013;161(1):68–75.PubMedCrossRef Mascarenhas J, Lu M, Li T, Petersen B, Hochman T, Najfeld V, et al. A phase I study of panobinostat (LBH589) in patients with primary myelofibrosis (PMF) and post-polycythaemia vera/essential thrombocythaemia myelofibrosis (post-PV/ET MF). BJH. 2013;161(1):68–75.PubMedCrossRef
54.
go back to reference Harrison C, Kiladjian JJ, Passamonti F, Vannucchi A, Acharyya S, Woo M, et al. A phase 1B, dose-finding study of ruxolitinib plus panobinostat in patients with primary myelofibrosis (MF), post-polycythemia vera MF (PPV-MF), or post-essential thrombocythemia MF (PET-MF) [abstract]. Haematol EHA Abstr Book. 2012;97(s1):146. Harrison C, Kiladjian JJ, Passamonti F, Vannucchi A, Acharyya S, Woo M, et al. A phase 1B, dose-finding study of ruxolitinib plus panobinostat in patients with primary myelofibrosis (MF), post-polycythemia vera MF (PPV-MF), or post-essential thrombocythemia MF (PET-MF) [abstract]. Haematol EHA Abstr Book. 2012;97(s1):146.
55.
go back to reference Akada H, Akada S, Gajra A, Bair A, Graziano S, Hutchison RE, et al. Efficacy of vorinostat in a murine model of polycythemia vera. Blood. 2012;119(16):3779–89.PubMedCrossRef Akada H, Akada S, Gajra A, Bair A, Graziano S, Hutchison RE, et al. Efficacy of vorinostat in a murine model of polycythemia vera. Blood. 2012;119(16):3779–89.PubMedCrossRef
56.
go back to reference Andersen CL, McMullin MF, Ejerblad E, Zweegman S, Harrison C, Fernandes S, et al. A phase II study of vorinostat (MK-0683) in patients with polycythaemia vera and essential thrombocythaemia. BJH. 2013. doi:10.1111/bjh.12416 [Epub ahead of print].PubMed Andersen CL, McMullin MF, Ejerblad E, Zweegman S, Harrison C, Fernandes S, et al. A phase II study of vorinostat (MK-0683) in patients with polycythaemia vera and essential thrombocythaemia. BJH. 2013. doi:10.​1111/​bjh.​12416 [Epub ahead of print].PubMed
57.
go back to reference Finazzi G, Vannucchi AM, Martinelli V, Ruggeri M, Nobile F, Specchia G, et al. A phase II study of Givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapy. BJH. 2013;161(5):688–94.PubMedCrossRef Finazzi G, Vannucchi AM, Martinelli V, Ruggeri M, Nobile F, Specchia G, et al. A phase II study of Givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapy. BJH. 2013;161(5):688–94.PubMedCrossRef
58.
go back to reference Gao SM, Chen CQ, Wang LY, Hong LL, Wu JB, Dong PH, et al. Histone deacetylases inhibitor sodium butyrate inhibits JAK2/STAT signaling through upregulation of SOCS1 and SOCS3 mediated by HDAC8 inhibition in myeloproliferative neoplasms. Exp Hematol. 2013;41(3):261–70.PubMedCrossRef Gao SM, Chen CQ, Wang LY, Hong LL, Wu JB, Dong PH, et al. Histone deacetylases inhibitor sodium butyrate inhibits JAK2/STAT signaling through upregulation of SOCS1 and SOCS3 mediated by HDAC8 inhibition in myeloproliferative neoplasms. Exp Hematol. 2013;41(3):261–70.PubMedCrossRef
59.
60.
go back to reference Mullally A, Bruedigam C, Poveromo L, Heidel FH, Purdon A, Vu T, et al. Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-α in a murine model of polycythemia vera. Blood. 2013;121(18):3692–702.PubMedCrossRef Mullally A, Bruedigam C, Poveromo L, Heidel FH, Purdon A, Vu T, et al. Depletion of Jak2V617F myeloproliferative neoplasm-propagating stem cells by interferon-α in a murine model of polycythemia vera. Blood. 2013;121(18):3692–702.PubMedCrossRef
61.
go back to reference Quintás-Cardama A, Kantarjian H, Manshouri T, Luthra R, Estrov Z, Pierce S, et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol. 2009;27(32):5418–24.PubMedCrossRef Quintás-Cardama A, Kantarjian H, Manshouri T, Luthra R, Estrov Z, Pierce S, et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol. 2009;27(32):5418–24.PubMedCrossRef
62.
go back to reference Staerk J, Lacout C, Sato T, Smith SO, Vainchenker W, Constantinescu SN. An amphipathic motif at the transmembrane-cytoplasmic junction prevents autonomous activation of the thrombopoietin receptor. Blood. 2006;107(5):1864–71.PubMedCrossRef Staerk J, Lacout C, Sato T, Smith SO, Vainchenker W, Constantinescu SN. An amphipathic motif at the transmembrane-cytoplasmic junction prevents autonomous activation of the thrombopoietin receptor. Blood. 2006;107(5):1864–71.PubMedCrossRef
63.
go back to reference Baerlocher GM, Leibundgut EO, Ayran C, Blaney M, Burington B, Morfeld D, et al. Imetelstat rapidly induces and maintains substantial hematologic and molecular responses in patients with Essential Thrombocythemia (ET) who are refractory or intolerant to prior therapy: preliminary phase II results [abstract]. ASH Annu Meet Abstra. 2012;120:179. Baerlocher GM, Leibundgut EO, Ayran C, Blaney M, Burington B, Morfeld D, et al. Imetelstat rapidly induces and maintains substantial hematologic and molecular responses in patients with Essential Thrombocythemia (ET) who are refractory or intolerant to prior therapy: preliminary phase II results [abstract]. ASH Annu Meet Abstra. 2012;120:179.
64.
go back to reference Nelson EA, Sharma SV, Settleman J, Frank DA. A chemical biology approach to developing STAT inhibitors: molecular strategies for accelerating clinical translation. Oncotarget. 2011;2(6):518–24.PubMed Nelson EA, Sharma SV, Settleman J, Frank DA. A chemical biology approach to developing STAT inhibitors: molecular strategies for accelerating clinical translation. Oncotarget. 2011;2(6):518–24.PubMed
65.
go back to reference Nelson EA, Walker SR, Weisberg E, Bar-Natan M, Barrett R, Gashin LB, et al. The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. Blood. 2011;117(12):3421–9.PubMedCrossRef Nelson EA, Walker SR, Weisberg E, Bar-Natan M, Barrett R, Gashin LB, et al. The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors. Blood. 2011;117(12):3421–9.PubMedCrossRef
Metadata
Title
Molecular Classification of Myeloproliferative Neoplasms—Pros and Cons
Authors
Moosa Qureshi
Claire Harrison
Publication date
01-12-2013
Publisher
Springer US
Published in
Current Hematologic Malignancy Reports / Issue 4/2013
Print ISSN: 1558-8211
Electronic ISSN: 1558-822X
DOI
https://doi.org/10.1007/s11899-013-0179-9

Other articles of this Issue 4/2013

Current Hematologic Malignancy Reports 4/2013 Go to the issue

Myelodysplastic Syndromes (M Sekeres, Section Editor)

Febrile Neutropenia in Hematologic Malignancies

Multiple Myeloma (R Niesvizky, Section Editor)

New Insights and Modern Treatment of AL Amyloidosis

Myeloproliferative Disorders (JJ Kiladjian, Section Editor)

The New Landscape of Therapy for Myelofibrosis

Myeloproliferative Disorders (JJ Kiladjian, Section Editor)

WHO Classification of Myeloproliferative Neoplasms (MPN): A Critical Update

Myeloproliferative Disorders (JJ Kiladjian, Section Editor)

Are MPNs Vascular Diseases?

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.