JAK2 V617F in Myeloid Disorders: Molecular Diagnostic Techniques and Their Clinical Utility
2006; Elsevier BV; Volume: 8; Issue: 4 Linguagem: Inglês
10.2353/jmoldx.2006.060007
ISSN1943-7811
Autores Tópico(s)Chronic Myeloid Leukemia Treatments
ResumoIn early 2005, several groups of investigators studying myeloid malignancies described a novel somatic point mutation (V617F) in the conserved autoinhibitory pseudokinase domain of the Janus kinase 2 (JAK2) protein, which plays an important role in normal hematopoietic growth factor signaling. The V617F mutation is present in blood and marrow from a large proportion of patients with classic BCR/ABL-negative chronic myeloproliferative disorders and of a few patients with other clonal hematological diseases such as myelodysplastic syndrome, atypical myeloproliferative disorders, and acute myeloid leukemia. The JAK2 V617F mutation causes constitutive activation of the kinase, with deregulated intracellular signaling that mimics continuous hematopoietic growth factor stimulation. Within 7 months of the first electronic publication describing this new mutation, clinical molecular diagnostic laboratories in the United States and Europe began offering JAK2 mutation testing on a fee-for-service basis. Here, I review the various techniques used by research groups and clinical laboratories to detect the genetic mutation underlying JAK2 V617F, including fluorescent dye chemistry sequencing, allele-specific polymerase chain reaction (PCR), real-time PCR, DNA-melting curve analysis, pyrosequencing, and others. I also discuss diagnostic sensitivity, performance, and other practical concerns relevant to the clinical laboratorian in addition to the potential diagnostic utility of JAK2 mutation tests. In early 2005, several groups of investigators studying myeloid malignancies described a novel somatic point mutation (V617F) in the conserved autoinhibitory pseudokinase domain of the Janus kinase 2 (JAK2) protein, which plays an important role in normal hematopoietic growth factor signaling. The V617F mutation is present in blood and marrow from a large proportion of patients with classic BCR/ABL-negative chronic myeloproliferative disorders and of a few patients with other clonal hematological diseases such as myelodysplastic syndrome, atypical myeloproliferative disorders, and acute myeloid leukemia. The JAK2 V617F mutation causes constitutive activation of the kinase, with deregulated intracellular signaling that mimics continuous hematopoietic growth factor stimulation. Within 7 months of the first electronic publication describing this new mutation, clinical molecular diagnostic laboratories in the United States and Europe began offering JAK2 mutation testing on a fee-for-service basis. Here, I review the various techniques used by research groups and clinical laboratories to detect the genetic mutation underlying JAK2 V617F, including fluorescent dye chemistry sequencing, allele-specific polymerase chain reaction (PCR), real-time PCR, DNA-melting curve analysis, pyrosequencing, and others. I also discuss diagnostic sensitivity, performance, and other practical concerns relevant to the clinical laboratorian in addition to the potential diagnostic utility of JAK2 mutation tests. In March and April of 2005, multiple research groups with an interest in myeloid neoplasia reported a new and exciting insight into the pathobiology of myeloproliferative disorders (MPDs): the widespread occurrence of a somatic, acquired point mutation in a highly conserved residue of the autoinhibitory domain of the Janus kinase 2 (JAK2) tyrosine kinase.1James C Ugo V Le Couedic J-P Staerk J Delhommeau F Lacout C Garcon L Raslova H Berger R Bennaceur-Griscelli A Villeval JL Constantinescu SN Casadevall N Vainchenker W A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.Nature. 2005; 434: 1144-1148Crossref PubMed Scopus (2846) Google Scholar2Kralovics R Passamonti F Buser AS Teo S-S Tiedt R Passweg JR Tichelli A Cazzola M Skoda RC A gain-of-function mutation of JAK2 in myeloproliferative disorders.N Engl J Med. 2005; 352: 1779-1790Crossref PubMed Scopus (2897) Google Scholar3Levine RL Wadleigh M Cools J Ebert BL Wernig G Huntly BJP Boggon TJ Wlodarska I Clark JJ Moore S Adelsperger J Koo S Lee JC Gabriel S Mercher T D'Andrea A Frohling S Dohner K Marynen P Vandenberghe P Mesa RA Tefferi A Griffin JD Eck MJ Sellers WR Meyerson M Golub TR Lee SJ Gilliland DG Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.Cancer Cell. 2005; 7: 387-397Abstract Full Text Full Text PDF PubMed Scopus (2409) Google Scholar4Baxter 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 Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.The Lancet. 2005; 365: 1054-1061Abstract Full Text Full Text PDF PubMed Scopus (2296) Google Scholar5Zhao R Xing S Li Z Fu X Li Q Krantz SB Zhao ZJ Identification of an acquired JAK2 mutation in Polycythemia vera.J Biol Chem. 2005; 280: 22788-22792Crossref PubMed Scopus (546) Google Scholar Before this discovery, several other tyrosine kinase mutations had been associated with myeloid malignancies,6Reilly JT Receptor tyrosine kinases in normal and malignant haematopoiesis.Blood Rev. 2003; 17: 241-248Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar but the key signaling abnormalities in most of the BCR/ABL-negative myeloproliferative disorders remained mysterious. The remarkable clinical success with the drug imatinib mesylate, a BCR/ABL kinase inhibitor active in chronic myeloid leukemia and in several rarer forms of myeloid neoplasia, spurred great interest in this line of investigation.7Druker BJ Talpaz M Resta DJ Peng B Buchdunger E Ford JM Lydon NB Kantarjian H Capdeville R Ohno-Jones S Sawyers CL Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.N Engl J Med. 2001; 344: 1031-1037Crossref PubMed Scopus (4388) Google Scholar,8Hannah AL Kinases as drug discovery targets in hematologic malignancies.Curr Mol Med. 2005; 5: 625-642Crossref PubMed Scopus (24) Google Scholar The specific genetic mutation observed, c.1849 G>T (GenBank accession no. NM_004972; mutations are described herein using the proposed standard nomenclature of den Dunnen and Antonarakis9den Dunnen JT Antonarakis SE Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion.Hum Mutat. 2000; 15: 7-12Crossref PubMed Scopus (1503) Google Scholar), results in substitution of phenylalanine for valine, both hydrophobic nonpolar amino acids, at position 617 of the JAK2 protein (p.V617F, hereafter referred to simply as V617F), within the JH2 pseudokinase domain.10Nelson ME Steensma DP JAK2 V617F in myeloid disorders: what do we know now, and where are we headed?.Leuk Lymphoma. 2006; 47: 177-194Crossref PubMed Scopus (47) Google Scholar Loss of JAK2 autoinhibition results in constitutive activation of the kinase, analogous to other mutations in MPDs and leukemia that aberrantly activate tyrosine kinases.1James C Ugo V Le Couedic J-P Staerk J Delhommeau F Lacout C Garcon L Raslova H Berger R Bennaceur-Griscelli A Villeval JL Constantinescu SN Casadevall N Vainchenker W A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.Nature. 2005; 434: 1144-1148Crossref PubMed Scopus (2846) Google Scholar,11De Keersmaecker K Cools J Chronic myeloproliferative disorders: a tyrosine kinase tale.Leukemia. 2005; 20: 200-205Crossref Scopus (67) Google Scholar,12Kaushansky K On the molecular origins of the chronic myeloproliferative disorders: it all makes sense.Blood. 2005; 105: 4187-4190Crossref PubMed Scopus (120) Google Scholar Because JAK2 is normally responsible for signaling from various growth factor receptors (Figure 1), including those for erythropoietin and thrombopoietin, this mutation results in deregulated intracellular signaling with cell proliferation that is independent of normal growth factor control (eg, abnormal “endogenous” erythroid colony growth in vitro and erythrocytosis in mice transfected with the mutant gene). In the original patient series that appeared in early 2005, JAK2 V617F was found in 65 to 97% of patients with clonal polycythemia vera (PV) (overall detection rate 74%), in 23 to 57% of samples from patients with essential thrombocythemia (ET) (overall, 36%), and in 35 to 57% of those with chronic idiopathic myelofibrosis (IMF) (overall, 44%) (reviewed in Refs. 10Nelson ME Steensma DP JAK2 V617F in myeloid disorders: what do we know now, and where are we headed?.Leuk Lymphoma. 2006; 47: 177-194Crossref PubMed Scopus (47) Google Scholar and 13Tefferi A Gilliland DG The JAK2V617F tyrosine kinase mutation in myeloproliferative disorders: status report and immediate implications for disease classification and diagnosis.Mayo Clin Proc. 2005; 80: 947-958Abstract Full Text Full Text PDF PubMed Google Scholar). Most series used the 2001 World Health Organization clinicopathological diagnostic criteria for hematopoietic neoplasms14Jaffe ES Harris NL Stein H Vardiman JW World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Hematopoietic and Lymphoid Tissues. IARC Press, Lyon, France2001Google Scholar,15Vardiman JW Harris NL Brunning RD The World Health Organization (WHO) classification of the myeloid neoplasms.Blood. 2002; 100: 2292-2302Crossref PubMed Scopus (1776) Google Scholar as the “gold standard” for purposes of determining sensitivity and specificity of the JAK2 mutation. The relationship of the mutation to MPD cases classified using the older Polycythemia Vera Study Group diagnostic criteria16Pearson TC Messinezy M The diagnostic criteria of polycythaemia rubra vera.Leuk Lymphoma. 1996; 22: 87-93PubMed Google Scholar was similar.17James C Delhommeau F Marzac C Teyssandier I Couedic JP Giraudier S Roy L Saulnier P Lacroix L Maury S Tulliez M Vainchenker W Ugo V Casadevall N Detection of JAK2 V617F as a first intention diagnostic test for erythrocytosis.Leukemia. 2006; 20: 350-353Crossref PubMed Scopus (86) Google Scholar A flurry of papers describing the prevalence of the JAK2 V617F in various disease subsets and clinical correlates of the mutation quickly followed these seminal reports. As a barometer of this activity, it is notable that there were 502 PubMed-accessible articles on JAK2 published in 2004, compared with more than 1200 in 2005 (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?DB=pubmed; accessed January 9, 2006). The subsequent studies confirmed the strong link between the mutation and classic BCR/ABL-negative MPDs but also detected the JAK2 V617F mutation in rare cases of other clonal myeloid disorders (reviewed in Ref. 18James C Ugo V Casadevall N Constantinescu SN Vainchenker W A JAK2 mutation in myeloproliferative disorders: pathogenesis and therapeutic and scientific prospects.Trends Mol Med. 2005; 11: 546-554Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar) The latter included subtypes of myelodysplastic syndrome (MDS),19Steensma DP Dewald GW Lasho TL Powell HL McClure RF Levine RL Gilliland DG Tefferi A The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes.Blood. 2005; 106: 1207-1209Crossref PubMed Scopus (316) Google Scholar chronic myelomonocytic leukemia,19Steensma DP Dewald GW Lasho TL Powell HL McClure RF Levine RL Gilliland DG Tefferi A The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes.Blood. 2005; 106: 1207-1209Crossref PubMed Scopus (316) Google Scholar20Levine RL Loriaux M Huntly BJ Loh ML Beran M Stoffregen E Berger R Clark JJ Willis SG Nguyen KT Flores NJ Estey E Gattermann N Armstrong S Look AT Griffin JD Bernard OA Heinrich MC Gilliland DG Druker B Deininger MWN The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia.Blood. 2005; 106: 3377-3379Crossref PubMed Scopus (318) Google Scholar21Jelinek J Oki Y Gharibyan V Bueso-Ramos C Prchal JT Verstovsek S Beran M Estey E Kantarjian HM Issa JP JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocytic leukemia.Blood. 2005; 106: 3370-3373Crossref PubMed Scopus (317) Google Scholar acute myeloid leukemia (AML, especially AML arising from MPD20Levine RL Loriaux M Huntly BJ Loh ML Beran M Stoffregen E Berger R Clark JJ Willis SG Nguyen KT Flores NJ Estey E Gattermann N Armstrong S Look AT Griffin JD Bernard OA Heinrich MC Gilliland DG Druker B Deininger MWN The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia.Blood. 2005; 106: 3377-3379Crossref PubMed Scopus (318) Google Scholar21Jelinek J Oki Y Gharibyan V Bueso-Ramos C Prchal JT Verstovsek S Beran M Estey E Kantarjian HM Issa JP JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocytic leukemia.Blood. 2005; 106: 3370-3373Crossref PubMed Scopus (317) Google Scholar22Lee JW Kim YG Soung YH Han KJ Kim SY Rhim HS Min WS Nam SW Park WS Lee JY Yoo NJ Lee SH The JAK2 V617F mutation in de novo acute myelogenous leukemias.Oncogene. 2006; 25: 1434-1436Crossref PubMed Scopus (81) Google Scholar23Frohling S Lipka DB Kayser S Scholl C Schlenk RF Dohner H Gilliland DG Levine RL Dohner K Rare occurrence of the JAK2 V617F mutation in AML subtypes M5, M6, and M7.Blood. 2006; 107: 1242-1243Crossref PubMed Scopus (53) Google Scholar), systemic mastocytosis,19Steensma DP Dewald GW Lasho TL Powell HL McClure RF Levine RL Gilliland DG Tefferi A The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes.Blood. 2005; 106: 1207-1209Crossref PubMed Scopus (316) Google Scholar hypereosinophilic syndrome,19Steensma DP Dewald GW Lasho TL Powell HL McClure RF Levine RL Gilliland DG Tefferi A The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes.Blood. 2005; 106: 1207-1209Crossref PubMed Scopus (316) Google Scholar,24Jones AV Kreil S Zoi K Waghorn K Curtis C Zhang L Score J Seear R Chase AJ Grand FH White H Zoi C Loukopoulos D Terpos E Vervessou EC Schultheis B Emig M Ernst T Lengfelder E Hehlmann R Hochhaus A Oscier D Silver RT Reiter A Cross NC Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders.Blood. 2005; 106: 2162-2168Crossref PubMed Scopus (497) Google Scholar chronic neutrophilic leukemia,19Steensma DP Dewald GW Lasho TL Powell HL McClure RF Levine RL Gilliland DG Tefferi A The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and myelodysplastic syndromes.Blood. 2005; 106: 1207-1209Crossref PubMed Scopus (316) Google Scholar,25McLornan DP Percy MJ Jones AV Cross NC Mc Mullin MF Chronic neutrophilic leukemia with an associated V617F JAK2 tyrosine kinase mutation.Haematologica. 2005; 90: 1696-1697PubMed Google Scholar atypical CML,21Jelinek J Oki Y Gharibyan V Bueso-Ramos C Prchal JT Verstovsek S Beran M Estey E Kantarjian HM Issa JP JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocytic leukemia.Blood. 2005; 106: 3370-3373Crossref PubMed Scopus (317) Google Scholar juvenile myelomonocytic leukemia,26Tono C Xu G Toki T Takahashi Y Sasaki S Terui K Ito E JAK2 Val617Phe activating tyrosine kinase mutation in juvenile myelomonocytic leukemia.Leukemia. 2005; 19: 1843-1844Crossref PubMed Scopus (29) Google Scholar MDS with fibrosis,27Ohyashiki K Aota Y Akahane D Gotoh A Miyazawa K Kimura Y Ohyashiki JH The JAK2 V617F tyrosine kinase mutation in myelodysplastic syndromes (MDS) developing myelofibrosis indicates the myeloproliferative nature in a subset of MDS patients.Leukemia. 2005; 19: 2359-2360Crossref PubMed Scopus (48) Google Scholar the World Health Organization provisional entity refractory anemia with ringed sideroblasts with thrombocytosis (RARS-T),28Szpurka H Tiu R Hsi E Lichtin AE Sekeres MA Theil KS Maciejewski JP Presence of JAK2 mutations in MDS/MPD-u WHO classified patients and not other forms of MDS suggests their derivation from classical myeloproliferative syndrome (Abstract 369).Blood. 2005; 106: 112aGoogle Scholar,29Shaw GR Ringed sideroblasts with thrombocytosis: an uncommon mixed myelodysplastic/myeloproliferative disease of older adults.Br J Haematol. 2005; 131: 180-184PubMed Google Scholar and various unclassifiable MDS/MPD cases.24Jones AV Kreil S Zoi K Waghorn K Curtis C Zhang L Score J Seear R Chase AJ Grand FH White H Zoi C Loukopoulos D Terpos E Vervessou EC Schultheis B Emig M Ernst T Lengfelder E Hehlmann R Hochhaus A Oscier D Silver RT Reiter A Cross NC Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders.Blood. 2005; 106: 2162-2168Crossref PubMed Scopus (497) Google Scholar Why the same mutation should be associated with such diverse phenotypes remains an unanswered question10Nelson ME Steensma DP JAK2 V617F in myeloid disorders: what do we know now, and where are we headed?.Leuk Lymphoma. 2006; 47: 177-194Crossref PubMed Scopus (47) Google Scholar,18James C Ugo V Casadevall N Constantinescu SN Vainchenker W A JAK2 mutation in myeloproliferative disorders: pathogenesis and therapeutic and scientific prospects.Trends Mol Med. 2005; 11: 546-554Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar and is a subject of active investigation. To date, the V617F mutation has not been found in any of more than 700 healthy persons tested10Nelson ME Steensma DP JAK2 V617F in myeloid disorders: what do we know now, and where are we headed?.Leuk Lymphoma. 2006; 47: 177-194Crossref PubMed Scopus (47) Google Scholar,30McClure R Mai M Lasho T Validation of two clinically useful assays for evaluation of JAK2 V617F mutation in chronic myeloproliferative disorders.Leukemia. 2006; 20: 168-171Crossref PubMed Scopus (88) Google Scholar nor in any patients with secondary (reactive) blood count abnormalities mimicking clonal myeloproliferation. This specificity is of great importance because there is considerable clinical overlap between reactive cellular proliferations and clonal myeloproliferative disorders, making a definitive diagnosis challenging in some cases; a 100% specific test of even moderate sensitivity would be of marked help to clinicians. Likewise, there have been no convincing descriptions of germline JAK2 mutations in patients with hematopoietic malignancies, including families with multiple members with MPDs.31Bellanne-Chantelot C Labopin M Chaumarel I Delhommeau F Leroy G Bellanger F Thomas G Vainchenker W Najman A Heterogeneous distribution of the JAK2 Val617Phe activating mutation in familial myeloproliferative disorders (Abstract 115).Blood. 2005; 106: 38aGoogle Scholar In the few instances in which the V617F mutation was present in buccal cells in a MPD patient, the mutation was not present in hair follicles,1James C Ugo V Le Couedic J-P Staerk J Delhommeau F Lacout C Garcon L Raslova H Berger R Bennaceur-Griscelli A Villeval JL Constantinescu SN Casadevall N Vainchenker W A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.Nature. 2005; 434: 1144-1148Crossref PubMed Scopus (2846) Google Scholar,3Levine RL Wadleigh M Cools J Ebert BL Wernig G Huntly BJP Boggon TJ Wlodarska I Clark JJ Moore S Adelsperger J Koo S Lee JC Gabriel S Mercher T D'Andrea A Frohling S Dohner K Marynen P Vandenberghe P Mesa RA Tefferi A Griffin JD Eck MJ Sellers WR Meyerson M Golub TR Lee SJ Gilliland DG Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.Cancer Cell. 2005; 7: 387-397Abstract Full Text Full Text PDF PubMed Scopus (2409) Google Scholar suggesting contamination of the buccal cell collection by blood cells. In addition, JAK2 V617F has not been detected in patients with acute lymphoblastic leukemia,20Levine RL Loriaux M Huntly BJ Loh ML Beran M Stoffregen E Berger R Clark JJ Willis SG Nguyen KT Flores NJ Estey E Gattermann N Armstrong S Look AT Griffin JD Bernard OA Heinrich MC Gilliland DG Druker B Deininger MWN The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia.Blood. 2005; 106: 3377-3379Crossref PubMed Scopus (318) Google Scholar,32Kratz CP Boll S Kontny U Schrappe M Niemeyer CM Stanulla M Mutational screen reveals a novel JAK2 mutation, L611S, in a child with acute lymphoblastic leukemia.Leukemia. 2006; 20: 381-383Crossref PubMed Scopus (57) Google Scholar B-cell lymphoproliferative disorders,20Levine RL Loriaux M Huntly BJ Loh ML Beran M Stoffregen E Berger R Clark JJ Willis SG Nguyen KT Flores NJ Estey E Gattermann N Armstrong S Look AT Griffin JD Bernard OA Heinrich MC Gilliland DG Druker B Deininger MWN The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia.Blood. 2005; 106: 3377-3379Crossref PubMed Scopus (318) Google Scholar,33Steensma DP Dewald GW Lasho TL Powell HL McClure RF Levine RL Gilliland DG Tefferi A The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both “atypical” myeloproliferative disorders and the myelodysplastic syndrome.Blood. 2005; 106: 1207-1209Crossref PubMed Scopus (404) Google Scholar,34Scott LM Campbell PJ Baxter EJ Todd T Stephens P Edkins S Wooster R Stratton MR Futreal PA Green AR The V617F JAK2 mutation is uncommon in cancers and in myeloid malignancies other than the classic myeloproliferative disorders.Blood. 2005; 106: 2920-2921Crossref PubMed Scopus (131) Google Scholar multiple myeloma,34Scott LM Campbell PJ Baxter EJ Todd T Stephens P Edkins S Wooster R Stratton MR Futreal PA Green AR The V617F JAK2 mutation is uncommon in cancers and in myeloid malignancies other than the classic myeloproliferative disorders.Blood. 2005; 106: 2920-2921Crossref PubMed Scopus (131) Google Scholar or various solid tumors.34Scott LM Campbell PJ Baxter EJ Todd T Stephens P Edkins S Wooster R Stratton MR Futreal PA Green AR The V617F JAK2 mutation is uncommon in cancers and in myeloid malignancies other than the classic myeloproliferative disorders.Blood. 2005; 106: 2920-2921Crossref PubMed Scopus (131) Google Scholar It has also not been observed in patients with myeloproliferation who have other activating tyrosine kinase mutations underlying the cell growth (eg, BCR/ABL fusion, FLT3 p.D835 mutations or juxtamembrane-domain internal tandem duplication, or c-KIT p.D816V mutation).35Jones AV Kreil S Zoi K Waghorn K Curtis C Zhang L Score J Seear R Chase AJ Grand FH White H Zoi C Loukopoulos D Terpos E Vervessou EC Schultheis B Emig M Ernst T Lengfelder E Hehlmann R Hochhaus A Oscier D Silver RT Reiter A Cross NC Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders.Blood. 2005; 106: 2162-2168Crossref PubMed Scopus (727) Google Scholar These observations suggest that JAK2 V617F is specific for myeloid lineage proliferation36Tefferi A Lasho TL Schwager SM Steensma DP Mesa RA Li CY Wadleigh M Gilliland D Gary The JAK2(V617F) tyrosine kinase mutation in myelofibrosis with myeloid metaplasia: lineage specificity and clinical correlates.Br J Haematol. 2005; 131: 320-328Crossref PubMed Scopus (199) Google Scholar and that it may be mutually exclusive of most other activating tyrosine kinase mutations. In most cases of ET and IMF, patient samples contain both wild-type and mutant JAK2 genomic DNA and transcripts. This may be due to mixed clonality, with residual normal hematopoietic elements and contaminating nonclonal tissues such as lymphocytes admixed with mutant clones, or it may be due to heterozygosity for the autosomal mutation (encoded on chromosome 9p24).10Nelson ME Steensma DP JAK2 V617F in myeloid disorders: what do we know now, and where are we headed?.Leuk Lymphoma. 2006; 47: 177-194Crossref PubMed Scopus (47) Google Scholar In contrast, rare patients with ET (ie, <10% of patients) and with IMF and approximately one-third of PV patients have samples containing only the mutant allele and have been referred to as homozygous for the mutation.1James C Ugo V Le Couedic J-P Staerk J Delhommeau F Lacout C Garcon L Raslova H Berger R Bennaceur-Griscelli A Villeval JL Constantinescu SN Casadevall N Vainchenker W A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.Nature. 2005; 434: 1144-1148Crossref PubMed Scopus (2846) Google Scholar,2Kralovics R Passamonti F Buser AS Teo S-S Tiedt R Passweg JR Tichelli A Cazzola M Skoda RC A gain-of-function mutation of JAK2 in myeloproliferative disorders.N Engl J Med. 2005; 352: 1779-1790Crossref PubMed Scopus (2897) Google Scholar,4Baxter 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 Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.The Lancet. 2005; 365: 1054-1061Abstract Full Text Full Text PDF PubMed Scopus (2296) Google Scholar,35Jones AV Kreil S Zoi K Waghorn K Curtis C Zhang L Score J Seear R Chase AJ Grand FH White H Zoi C Loukopoulos D Terpos E Vervessou EC Schultheis B Emig M Ernst T Lengfelder E Hehlmann R Hochhaus A Oscier D Silver RT Reiter A Cross NC Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders.Blood. 2005; 106: 2162-2168Crossref PubMed Scopus (727) Google Scholar Several analyses, including microsatellite analysis and fluorescent in situ hybridization, revealed that homozygosity for the JAK2 mutation arises by mitotic recombination, resulting in uniparental disomy.1James C Ugo V Le Couedic J-P Staerk J Delhommeau F Lacout C Garcon L Raslova H Berger R Bennaceur-Griscelli A Villeval JL Constantinescu SN Casadevall N Vainchenker W A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.Nature. 2005; 434: 1144-1148Crossref PubMed Scopus (2846) Google Scholar,2Kralovics R Passamonti F Buser AS Teo S-S Tiedt R Passweg JR Tichelli A Cazzola M Skoda RC A gain-of-function mutation of JAK2 in myeloproliferative disorders.N Engl J Med. 2005; 352: 1779-1790Crossref PubMed Scopus (2897) Google Scholar,4Baxter 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 Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.The Lancet. 2005; 365: 1054-1061Abstract Full Text Full Text PDF PubMed Scopus (2296) Google Scholar,35Jones AV Kreil S Zoi K Waghorn K Curtis C Zhang L Score J Seear R Chase AJ Grand FH White H Zoi C Loukopoulos D Terpos E Vervessou EC Schultheis B Emig M Ernst T Lengfelder E Hehlmann R Hochhaus A Oscier D Silver RT Reiter A Cross NC Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders.Blood. 2005; 106: 2162-2168Crossref PubMed Scopus (727) Google Scholar,37Fitzgibbon J Smith LL Raghavan M Smith ML Debernardi S Skoulakis S Lillington D Lister TA Young BD Association between acquired uniparental disomy and homozygous gene mutation in acute myeloid leukemias.Cancer Res. 2005; 65: 9152-9154Crossref PubMed Scopus (192) Google Scholar The clinical significance of JAK2 V617F in patients with MPDs remains uncertain, at least in terms of influence of the mutation on the disease course, ie, on the incidence of clinically relevant complications and the time to disease progression or death. Because almost all patients with PV have JAK2 V617F (97% in one series4Baxter 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 Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.The Lancet. 2005; 365: 1054-1061Abstract Full Text Full Text PDF PubMed Scopus (2296) Google Scholar), it has been difficult to generate a well-defined comparison group of patients who have wild-type JAK2 exclusively yet can be convincingly diagnosed with bona fide PV. For other MPDs such as ET and IMF, in which the JAK2 mutation incidence is closer to 50%, comparisons can be made more easily. Several groups have described features including an increased hemoglobin level or neutrophil count,38Cheung B Radia D Pantelidis P Yadegarfar G Harrison C The presence of the JAK2 V617F mutation is associated with a higher haemoglobin and increased risk of thrombosis in essential thrombocythaemia.Br J Haematol. 2006; 132: 244-245Crossref PubMed Scopus (134) Google Scholar39Campbell PJ Scott LM Buck G Wheatley K East CL Marsden JT Duffy A Boyd EM Bench AJ Scott MA Vassiliou GS Milligan DW Smith SR Erber WN Bareford D Wilkins BS Reilly JT Harrison CN Green AR United Kingdom Myeloproliferative Disorders Study Group, Medical Research Council Adult Leukaemia Working Party, Australasian Leukaemia and Lymphoma Group Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study.Lancet. 2005; 366: 1945-1953Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar40Campbell PJ Griesshammer M Dohner K Dohner H Kusec R Hasselbalch HC Larsen TS Pallisgaard N Giraudier S Le Bousse-Kerdiles MC Desterke C Guerton B Dupriez B Bordessoule D Fenaux P Kiladjian JJ Viallard JF Briere J Harrison CN Green AR Reilly JT The V617F mutation in JAK2 is associated with poorer survival in idiopathic
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