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• W1715726021 abstract "JAK2V617F is sufficiently prevalent in BCR-ABL1-negative myeloproliferative neoplasms (MPNs) to be useful as a clonal marker. JAK2V617F mutation screening is indicated for the evaluation of erythrocytosis, thrombocytosis, splanchnic vein thrombosis, and otherwise unexplained BCR-ABL1-negative granulocytosis. However, the mutation does not provide additional value in the presence of unequivocal morphologic diagnosis, and its presence does not necessarily distinguish one MPN from another or provide useful prognostic information. In general, quantitative cell-based JAK2V617F mutation assays are preferred because the additional information obtained on mutant allele burden enhances diagnostic certainty and facilitates monitoring of response to treatment. JAK2 exon 12 mutation screening is indicated only in the presence of JAK2V617F-negative erythrocytosis that is associated with a subnormal serum erythropoietin level. MPL mutations are neither frequent nor specific enough to warrant their routine use for MPN diagnosis, but they may be useful in resolving specific diagnostic problems. The practice of en bloc screening for JAK2V617F, JAK2 exon 12, and MPL mutations is scientifically irrational and economically irresponsible. JAK2V617F is sufficiently prevalent in BCR-ABL1-negative myeloproliferative neoplasms (MPNs) to be useful as a clonal marker. JAK2V617F mutation screening is indicated for the evaluation of erythrocytosis, thrombocytosis, splanchnic vein thrombosis, and otherwise unexplained BCR-ABL1-negative granulocytosis. However, the mutation does not provide additional value in the presence of unequivocal morphologic diagnosis, and its presence does not necessarily distinguish one MPN from another or provide useful prognostic information. In general, quantitative cell-based JAK2V617F mutation assays are preferred because the additional information obtained on mutant allele burden enhances diagnostic certainty and facilitates monitoring of response to treatment. JAK2 exon 12 mutation screening is indicated only in the presence of JAK2V617F-negative erythrocytosis that is associated with a subnormal serum erythropoietin level. MPL mutations are neither frequent nor specific enough to warrant their routine use for MPN diagnosis, but they may be useful in resolving specific diagnostic problems. The practice of en bloc screening for JAK2V617F, JAK2 exon 12, and MPL mutations is scientifically irrational and economically irresponsible. Morphology is the cornerstone of current diagnosis and classification in myeloid malignancies.1Vardiman J.W. Thiele J. Arber D.A. Brunning R.D. Borowitz M.J. Porwit A. Harris N.L. Le Beau M.M. Hellstrom-Lindberg E. Tefferi A. Bloomfield C.D. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes.Blood. 2009; 114: 937-951Crossref PubMed Scopus (3452) Google Scholar Cytochemical, immunophenotypic, cytogenetic, and molecular data enhance diagnostic accuracy and form the basis for the World Health Organization classification of myeloid malignancies into five main categories2Swerdlow SH Campo E. Harris N.L. Jaffe E.S. Pileri S.A. Stein H. Thiele J. Vardiman J.W. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon, France2008Google Scholar: acute myeloid leukemia, myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), MDS/MPN overlap, and platelet-derived growth factor receptor gene or fibroblast growth factor receptor 1 gene rearranged myeloid/lymphoid neoplasms associated with eosinophilia. The World Health Organization MPN category includes eight subcategories: chronic myelogenous leukemia, polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), mastocytosis, chronic eosinophilic leukemia not otherwise specified, chronic neutrophilic leukemia, and MPN unclassifiable.1Vardiman J.W. Thiele J. Arber D.A. Brunning R.D. Borowitz M.J. Porwit A. Harris N.L. Le Beau M.M. Hellstrom-Lindberg E. Tefferi A. Bloomfield C.D. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes.Blood. 2009; 114: 937-951Crossref PubMed Scopus (3452) Google Scholar Among these subcategories, the first four (ie, chronic myelogenous leukemia, PV, ET, and PMF) are currently referred to as “classic” MPNs, because they were included in the original description of myeloproliferative disorders by William Dameshek.3Tefferi A. The history of myeloproliferative disorders: before and after Dameshek.Leukemia. 2008; 22: 3-13Crossref PubMed Scopus (66) Google Scholar In general, current evidence supports consideration of all myeloid malignancies, including MPN, as clonal stem cell diseases. JAK2 and MPL mutations occur across the spectrum of myeloid malignancies, including MPN, MDS, MDS/MPN, and acute myeloid leukemia (Table 1).4Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010; 24: 1128-1138Crossref PubMed Scopus (432) Google Scholar, 5Patnaik M.M. Lasho T.L. Finke C.M. Gangat N. Caramazza D. Holtan S.G. Pardanani A. Knudson R.A. Ketterling R.P. Chen D. Hoyer J.D. Hanson C.A. Tefferi A. WHO-defined ‘myelodysplastic syndrome with isolated del(5q)’ in 88 consecutive patients: survival data, leukemic transformation rates and prevalence of JAK2 MPL and IDH mutations.Leukemia. 2010; 24: 1283-1289Crossref PubMed Scopus (84) Google Scholar, 6Szpurka H. Tiu R. Murugesan G. Aboudola S. Hsi E.D. Theil K.S. Sekeres M.A. Maciejewski J.P. Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation.Blood. 2006; 108: 2173-2181Crossref PubMed Scopus (189) Google Scholar, 7Pardanani A.D. Levine R.L. Lasho T. Pikman Y. Mesa R.A. Wadleigh M. Steensma D.P. Elliott M.A. Wolanskyj A.P. Hogan W.J. McClure R.F. Litzow M.R. Gilliland D.G. Tefferi A. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients.Blood. 2006; 108: 3472-3476Crossref PubMed Scopus (838) Google Scholar These mutations are most prevalent in the BCR-ABL1-negative classic MPN (ie, PV, ET, and PMF), which are morphologically characterized by the absence of both cellular dysplasia and monocytosis and the presence of abnormal megakaryocytes that are increased in number and often found in clusters. Megakaryocyte morphology and degree of trilineage proliferation differ among the three BCR-ABL1-negative classic MPNs. Megakaryocytes are large, hyperlobulated, and mature appearing in ET8Tefferi A. Skoda R. Vardiman J.W. Myeloproliferative neoplasms: contemporary diagnosis using histology and genetics.Nature Rev. 2009; 6: 627-637Google Scholar; immature appearing with hyperchromatic and irregularly folded bulky nuclei in PMF8Tefferi A. Skoda R. Vardiman J.W. Myeloproliferative neoplasms: contemporary diagnosis using histology and genetics.Nature Rev. 2009; 6: 627-637Google Scholar; and pleomorphic without maturation defects in PV.9Kvasnicka H.M. Thiele J. Prodromal myeloproliferative neoplasms: the 2008 WHO classification.Am J Hematol. 2010; 85: 62-69PubMed Google Scholar, 10Thiele J. Kvasnicka H.M. Vardiman J. Bone marrow histopathology in the diagnosis of chronic myeloproliferative disorders: a forgotten pearl.Best Pract Res Clin Haematol. 2006; 19: 413-437Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Megakaryocyte changes in BCR-ABL1-negative MPN are accompanied by left-shifted granulocyte proliferation in PMF, trilineage proliferation in PV, and otherwise normal-appearing bone marrow in ET. Overt bone marrow fibrosis is absent in prefibrotic PMF, which is otherwise characterized by the aforementioned PMF-associated changes in megakaryocyte morphology and increased granulocyte proliferation.11Thiele J. Kvasnicka H.M. Vardiman J.W. Orazi A. Franco V. Gisslinger H. Birgegard G. Griesshammer M. Tefferi A. Bone marrow fibrosis and diagnosis of essential thrombocythemia (letter to the editor).J Clin Oncol. 2009; 27 (author reply e222-223): e220-e221Crossref PubMed Scopus (26) Google Scholar Controversy is ongoing about the utility of morphology alone to distinguish ET from early PMF12Wilkins B.S. Erber W.N. Bareford D. Buck G. Wheatley K. East C.L. Paul B. Harrison C.N. Green A.R. Campbell P.J. Bone marrow pathology in essential thrombocythemia: interobserver reliability and utility for identifying disease subtypes.Blood. 2008; 111: 60-70Crossref PubMed Scopus (207) Google Scholar; however, this is irrelevant because clinical pathologists never base their diagnostic impressions on morphology alone, and they also consider clinical, cytogenetic, and molecular information.1Vardiman J.W. Thiele J. Arber D.A. Brunning R.D. Borowitz M.J. Porwit A. Harris N.L. Le Beau M.M. Hellstrom-Lindberg E. Tefferi A. Bloomfield C.D. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes.Blood. 2009; 114: 937-951Crossref PubMed Scopus (3452) Google Scholar, 11Thiele J. Kvasnicka H.M. Vardiman J.W. Orazi A. Franco V. Gisslinger H. Birgegard G. Griesshammer M. Tefferi A. Bone marrow fibrosis and diagnosis of essential thrombocythemia (letter to the editor).J Clin Oncol. 2009; 27 (author reply e222-223): e220-e221Crossref PubMed Scopus (26) Google ScholarTable 1Currently Known Mutations in BCR-ABL1-Negative Myeloproliferative NeoplasmsMutationsChromosome locationMutational frequency, %JAK29p24 PV∼964Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010; 24: 1128-1138Crossref PubMed Scopus (432) Google Scholar ET∼554Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010; 24: 1128-1138Crossref PubMed Scopus (432) Google Scholar PMF∼654Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010; 24: 1128-1138Crossref PubMed Scopus (432) Google Scholar BP-MPN∼504Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010; 24: 1128-1138Crossref PubMed Scopus (432) Google ScholarJAK2 exon 12 mutation [4]9p24 PV∼34Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010; 24: 1128-1138Crossref PubMed Scopus (432) Google ScholarMPL1p34 ET∼34Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010; 24: 1128-1138Crossref PubMed Scopus (432) Google Scholar PMF∼104Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010; 24: 1128-1138Crossref PubMed Scopus (432) Google Scholar BP-MPN∼54Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010; 24: 1128-1138Crossref PubMed Scopus (432) Google ScholarLNK12q24.12 PVRare20Pardanani A. Lasho T. Finke C. Oh S.T. Gotlib J. Tefferi A. LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2 IDH, JAK2 or MPL mutations.Leukemia. 2010; 24: 1713-1718Crossref PubMed Scopus (139) Google Scholar, 21Lasho T.L. Pardanani A. Tefferi A. LNK mutations in JAK2 mutation-negative erythrocytosis.N Engl J Med. 2010; 363: 1189-1190Crossref PubMed Scopus (116) Google Scholar ETRare19Oh S.T. Simonds E.F. Jones C. Hale M.B. Goltsev Y. Gibbs Jr, K.D. Merker J.D. Zehnder J.L. Nolan G.P. Gotlib J. Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms.Blood. 2010; 116: 988-992Crossref PubMed Scopus (258) Google Scholar, 20Pardanani A. Lasho T. Finke C. Oh S.T. Gotlib J. Tefferi A. LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2 IDH, JAK2 or MPL mutations.Leukemia. 2010; 24: 1713-1718Crossref PubMed Scopus (139) Google Scholar PMFRare19Oh S.T. Simonds E.F. Jones C. Hale M.B. Goltsev Y. Gibbs Jr, K.D. Merker J.D. Zehnder J.L. Nolan G.P. Gotlib J. Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms.Blood. 2010; 116: 988-992Crossref PubMed Scopus (258) Google Scholar, 20Pardanani A. Lasho T. Finke C. Oh S.T. Gotlib J. Tefferi A. LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2 IDH, JAK2 or MPL mutations.Leukemia. 2010; 24: 1713-1718Crossref PubMed Scopus (139) Google Scholar BP-MPN∼1020Pardanani A. Lasho T. Finke C. Oh S.T. Gotlib J. Tefferi A. LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2 IDH, JAK2 or MPL mutations.Leukemia. 2010; 24: 1713-1718Crossref PubMed Scopus (139) Google ScholarTET24q24 PV∼164Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010; 24: 1128-1138Crossref PubMed Scopus (432) Google Scholar ET∼54Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010; 24: 1128-1138Crossref PubMed Scopus (432) Google Scholar PMF∼174Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010; 24: 1128-1138Crossref PubMed Scopus (432) Google Scholar BP-MPN∼174Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010; 24: 1128-1138Crossref PubMed Scopus (432) Google ScholarASXL120q11.1 ET∼332Carbuccia N. Murati A. Trouplin V. Brecqueville M. Adelaide J. Rey J. Vainchenker W. Bernard O.A. Chaffanet M. Vey N. Birnbaum D. Mozziconacci M.J. Mutations of ASXL1 gene in myeloproliferative neoplasms.Leukemia. 2009; 23: 2183-2186Crossref PubMed Scopus (259) Google Scholar PMF∼13 BP-MPN∼18IDH1/IDH22q33.3/15q26.1 PV∼224Tefferi A. Lasho T.L. Abdel-Wahab O. Guglielmelli P. Patel J. Caramazza D. Pieri L. Finke C.M. Kilpivaara O. Wadleigh M. Mai M. McClure R.F. Gilliland D.G. Levine R.L. Pardanani A. Vannucchi A.M. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis.Leukemia. 2010; 24: 1302-1309Crossref PubMed Scopus (261) Google Scholar ET∼124Tefferi A. Lasho T.L. Abdel-Wahab O. Guglielmelli P. Patel J. Caramazza D. Pieri L. Finke C.M. Kilpivaara O. Wadleigh M. Mai M. McClure R.F. Gilliland D.G. Levine R.L. Pardanani A. Vannucchi A.M. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis.Leukemia. 2010; 24: 1302-1309Crossref PubMed Scopus (261) Google Scholar PMF∼424Tefferi A. Lasho T.L. Abdel-Wahab O. Guglielmelli P. Patel J. Caramazza D. Pieri L. Finke C.M. Kilpivaara O. Wadleigh M. Mai M. McClure R.F. Gilliland D.G. Levine R.L. Pardanani A. Vannucchi A.M. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis.Leukemia. 2010; 24: 1302-1309Crossref PubMed Scopus (261) Google Scholar BP-MPN∼2024Tefferi A. Lasho T.L. Abdel-Wahab O. Guglielmelli P. Patel J. Caramazza D. Pieri L. Finke C.M. Kilpivaara O. Wadleigh M. Mai M. McClure R.F. Gilliland D.G. Levine R.L. Pardanani A. Vannucchi A.M. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis.Leukemia. 2010; 24: 1302-1309Crossref PubMed Scopus (261) Google ScholarEZH27q36.1 PV∼334Ernst T. Chase A.J. Score J. Hidalgo-Curtis C.E. Bryant C. Jones A.V. Waghorn K. Zoi K. Ross F.M. Reiter A. Hochhaus A. Drexler H.G. Duncombe A. Cervantes F. Oscier D. Boultwood J. Grand F.H. Cross N.C. Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders.Nat Genet. 2010; 42: 722-726Crossref PubMed Scopus (931) Google Scholar PMF∼7DNMT3A2p23 PV∼735Stegelmann F. Bullinger L. Schlenk R.F. Paschka P. Griesshammer M. Blersch C. Kuhn S. Schauer S. Dohner H. Dohner K. DNMT3A mutations in myeloproliferative neoplasms.Leukemia. 2001; ([Epub ahead of press])https://doi.org/10.1038/leu.2011.77Crossref Scopus (133) Google Scholar PMF∼735Stegelmann F. Bullinger L. Schlenk R.F. Paschka P. Griesshammer M. Blersch C. Kuhn S. Schauer S. Dohner H. Dohner K. DNMT3A mutations in myeloproliferative neoplasms.Leukemia. 2001; ([Epub ahead of press])https://doi.org/10.1038/leu.2011.77Crossref Scopus (133) Google Scholar, 36Abdel-Wahab O. Pardanani A. Rampal R. Lasho T.L. Levine R.L. Tefferi A. DNMT3A mutational analysis in primary myelofibrosis, chronic myelomonocytic leukemia and advanced phases of myeloproliferative neoplasms (letter to the editor).Leukemia. 2011; 25: 1219-1220Crossref PubMed Scopus (116) Google Scholar BP-MPN∼1435Stegelmann F. Bullinger L. Schlenk R.F. Paschka P. Griesshammer M. Blersch C. Kuhn S. Schauer S. Dohner H. Dohner K. DNMT3A mutations in myeloproliferative neoplasms.Leukemia. 2001; ([Epub ahead of press])https://doi.org/10.1038/leu.2011.77Crossref Scopus (133) Google Scholar, 36Abdel-Wahab O. Pardanani A. Rampal R. Lasho T.L. Levine R.L. Tefferi A. DNMT3A mutational analysis in primary myelofibrosis, chronic myelomonocytic leukemia and advanced phases of myeloproliferative neoplasms (letter to the editor).Leukemia. 2011; 25: 1219-1220Crossref PubMed Scopus (116) Google ScholarCBL11q23.3 PVRare22Grand F.H. Hidalgo-Curtis C.E. Ernst T. Zoi K. Zoi C. McGuire C. Kreil S. Jones A. Score J. Metzgeroth G. Oscier D. Hall A. Brandts C. Serve H. Reiter A. Chase A.J. Cross N.C. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms.Blood. 2009; 113: 6182-6192Crossref PubMed Scopus (308) Google Scholar ETRare22Grand F.H. Hidalgo-Curtis C.E. Ernst T. Zoi K. Zoi C. McGuire C. Kreil S. Jones A. Score J. Metzgeroth G. Oscier D. Hall A. Brandts C. Serve H. Reiter A. Chase A.J. Cross N.C. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms.Blood. 2009; 113: 6182-6192Crossref PubMed Scopus (308) Google Scholar MF∼622Grand F.H. Hidalgo-Curtis C.E. Ernst T. Zoi K. Zoi C. McGuire C. Kreil S. Jones A. Score J. Metzgeroth G. Oscier D. Hall A. Brandts C. Serve H. Reiter A. Chase A.J. Cross N.C. Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms.Blood. 2009; 113: 6182-6192Crossref PubMed Scopus (308) Google ScholarIKZF17p12 CP-MPNRare27Jager R. Gisslinger H. Passamonti F. Rumi E. Berg T. Gisslinger B. Pietra D. Harutyunyan A. Klampfl T. Olcaydu D. Cazzola M. Kralovics R. Deletions of the transcription factor Ikaros in myeloproliferative neoplasms.Leukemia. 2010; 24: 1290-1298Crossref PubMed Scopus (102) Google Scholar BP-MPN∼1927Jager R. Gisslinger H. Passamonti F. Rumi E. Berg T. Gisslinger B. Pietra D. Harutyunyan A. Klampfl T. Olcaydu D. Cazzola M. Kralovics R. Deletions of the transcription factor Ikaros in myeloproliferative neoplasms.Leukemia. 2010; 24: 1290-1298Crossref PubMed Scopus (102) Google ScholarBP-MPN, blast-phase MPN; CP-MPN, chronic phase MPN; MF, both PMF and post-ET/PV myelofibrosis. Open table in a new tab BP-MPN, blast-phase MPN; CP-MPN, chronic phase MPN; MF, both PMF and post-ET/PV myelofibrosis. Clinically, PV and ET are characterized by erythrocytosis and thrombocytosis, respectively, and leukocytosis, splenomegaly, thrombohemorrhagic complications, vasomotor disturbances, pruritus, and a small risk of disease progression into acute leukemia or myelofibrosis.13Tefferi A. Essential thrombocythemia, polycythemia vera, and myelofibrosis: current management and the prospect of targeted therapy.Am J Hematol. 2008; 83: 491-497Crossref PubMed Scopus (74) Google Scholar PMF is characterized by anemia, splenomegaly, extramedullary hematopoiesis, constitutional symptoms, and a higher risk of leukemic progression.14Tefferi A. Myelofibrosis with myeloid metaplasia.N Engl J Med. 2000; 342: 1255-1265Crossref PubMed Scopus (651) Google Scholar Median survival exceeds 15 years in both ET and PV, but it is significantly shorter in PMF. The goal of therapy in PV and ET is to prevent thrombotic complications. Low-dose aspirin is the cornerstone of therapy in both PV and ET.15Landolfi R. Marchioli R. Kutti J. Gisslinger H. Tognoni G. Patrono C. Barbui T. Efficacy and safety of low-dose aspirin in polycythemia vera.N Engl J Med. 2004; 350: 114-124Crossref PubMed Scopus (782) Google Scholar In addition, phlebotomy is required in PV and hydroxyurea therapy in high-risk disease (history of thrombosis or age >60 years).13Tefferi A. Essential thrombocythemia, polycythemia vera, and myelofibrosis: current management and the prospect of targeted therapy.Am J Hematol. 2008; 83: 491-497Crossref PubMed Scopus (74) Google Scholar PMF is managed according to risk category from the Dynamic International Prognostic Scoring System.16Gangat N. Caramazza D. Vaidya R. George G. Begna K.H. Schwager S.M. Van Dyke D.L. Hanson C.A. Wu W. Pardanani A. Cervantes F. Passamonti F. Tefferi A. DIPSS-Plus: a refined Dynamic International Prognostic Scoring System (DIPSS) for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count and transfusion status.J Clin Oncol. 2011; 29: 392-397Crossref PubMed Scopus (711) Google Scholar Patients with low-risk or intermediate-1 PMF are managed by observation alone or conventional drug therapy, whereas allogeneic stem cell transplantation or experimental drug therapy might be necessary for intermediate-2 or high-risk disease. The disease-initiating mutation(s) in BCR-ABL1-negative MPN is unknown. However, JAK2V617F is present in most patients with PV, ET, or PMF, and a minority of patients with these diseases also harbor JAK2 exon 12, MPL, LNK, CBL, TET2, ASXL1, IDH, IKZF1, EZH2, or DNMT3A mutations (Table 1).4Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010; 24: 1128-1138Crossref PubMed Scopus (432) Google Scholar These mutations are currently thought to represent secondary events and to lack both disease specificity and mutual exclusivity. Some patients carry more than one mutation, and clonal hierarchy in such instances appears to be unpredictable.17Schaub F.X. Looser R. Li S. Hao-Shen H. Lehmann T. Tichelli A. Skoda R.C. Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms.Blood. 2010; 115: 2003-2007Crossref PubMed Scopus (148) Google Scholar JAK2 (Janus kinase 2) maps to chromosome 9p24. JAK2V617F is located on exon 14 and occurs in ∼96% of patients with PV, 55% with ET, and 65% with PMF.4Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010; 24: 1128-1138Crossref PubMed Scopus (432) Google Scholar JAK2V617F contributes to abnormal myeloproliferation in MPN, whereas such effect is erythroid lineage weighted with JAK2 exon 12 mutation.4Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010; 24: 1128-1138Crossref PubMed Scopus (432) Google Scholar MPL (myeloproliferative leukemia virus oncogene) maps to chromosome 1p34, and MPL mutations usually involve exon 10 and contribute to primarily megakaryocytic myeloproliferation.4Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010; 24: 1128-1138Crossref PubMed Scopus (432) Google Scholar MPL mutational frequencies are estimated at 3% in ET and 10% in PMF.4Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010; 24: 1128-1138Crossref PubMed Scopus (432) Google Scholar LNK (as in Links) maps to chromosome 12q24.12 and encodes for a membrane-bound adaptor protein that negatively regulates JAK2 signaling.18Gery S. Cao Q. Gueller S. Xing H. Tefferi A. Koeffler H.P. Lnk inhibits myeloproliferative disorder-associated JAK2 mutant. JAK2V617F.J Leukoc Biol. 2009; 85: 957-965Crossref PubMed Scopus (56) Google Scholar LNK mutations usually involve exon 2, are inactivating, and occur in ∼10% of patients with blast-phase MPN, whereas they are infrequent in chronic-phase disease.19Oh S.T. Simonds E.F. Jones C. Hale M.B. Goltsev Y. Gibbs Jr, K.D. Merker J.D. Zehnder J.L. Nolan G.P. Gotlib J. Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms.Blood. 2010; 116: 988-992Crossref PubMed Scopus (258) Google Scholar, 20Pardanani A. Lasho T. Finke C. Oh S.T. Gotlib J. Tefferi A. LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2 IDH, JAK2 or MPL mutations.Leukemia. 2010; 24: 1713-1718Crossref PubMed Scopus (139) Google Scholar, 21Lasho T.L. Pardanani A. Tefferi A. LNK mutations in JAK2 mutation-negative erythrocytosis.N Engl J Med. 2010; 363: 1189-1190Crossref PubMed Scopus (116) Google Scholar CBL (Casitas B-lineage lymphoma proto-oncogene) maps to chromosome 11q23.3, and its mutations involve exons 8 and 9.22Grand F.H. Hidalgo-Curtis C.E. Ernst T. Zoi K. Zoi C. McGuire C. Kreil S. Jones A. Score J. Metzgeroth G. Oscier D. Hall A. Brandts C. Serve H. Reiter A. Chase A.J. Cross N.C. 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Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms.Blood. 2009; 113: 6182-6192Crossref PubMed Scopus (308) Google Scholar IDH1 and IDH2 (isocitrate dehydrogenase) map to chromosomes 2q33.3 and 15q26.1, respectively, and their mutations involve exon 4.24Tefferi A. Lasho T.L. Abdel-Wahab O. Guglielmelli P. Patel J. Caramazza D. Pieri L. Finke C.M. Kilpivaara O. Wadleigh M. Mai M. McClure R.F. Gilliland D.G. Levine R.L. Pardanani A. Vannucchi A.M. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis.Leukemia. 2010; 24: 1302-1309Crossref PubMed Scopus (261) Google Scholar IDH mutations induce formation of 2-hydroxyglutarate, which is thought to be oncogenic.25Ward P.S. Patel J. Wise D.R. Abdel-Wahab O. Bennett B.D. Coller H.A. Cross J.R. Fantin V.R. Hedvat C.V. Perl A.E. Rabinowitz J.D. Carroll M. Su S.M. Sharp K.A. Levine R.L. Thompson C.B. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate.Cancer Cell. 2010; 17: 225-234Abstract Full Text Full Text PDF PubMed Scopus (1509) Google Scholar IDH mutational frequencies are estimated at 2% in PV, 1% in ET, 4% in PMF, and 20% in blast-phase MPN.24Tefferi A. Lasho T.L. Abdel-Wahab O. Guglielmelli P. Patel J. Caramazza D. Pieri L. Finke C.M. Kilpivaara O. Wadleigh M. Mai M. McClure R.F. Gilliland D.G. Levine R.L. Pardanani A. Vannucchi A.M. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis.Leukemia. 2010; 24: 1302-1309Crossref PubMed Scopus (261) Google Scholar IKAROS family zinc finger 1 (IKZF1) maps to chromosome 7p12 and is thought to function as a transcription regulator and tumor suppressor.26Trageser D. Iacobucci I. Nahar R. Duy C. von Levetzow G. Klemm L. Park E. Schuh W. Gruber T. Herzog S. Kim Y.M. Hofmann W.K. Li A. Storlazzi C.T. Jack H.M. Groffen J. Martinelli G. Heisterkamp N. Jumaa H. Muschen M. Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function.J Exp Med. 2009; 206: 1739-1753Crossref PubMed Scopus (106) Google Scholar IKZF1 mutations are rare in chronic-phase MPN but might be detected in ∼19% of patients with blast-phase MPN.27Jager R. Gisslinger H. Passamonti F. Rumi E. Ber" @default.
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