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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2768. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Colaizzo, D. Articles by Margaglione, M. Search for Related Content PubMed PubMed Citation Articles by Colaizzo, D. Articles by Margaglione, M. Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CORRESPONDENCE A new JAK2 gene mutation in patients with polycythemia vera and splanchnic vein thrombosis To the editor: Venous thrombosis is common in white individuals, affecting 1 out of 1000 individuals every year. The pathogenesis of venous thrombosis is multifactorial, involving acquired and genetic factors. Very recently, the JAK2 V617F mutation, an acquired somatic event occurring in most patients with polycythemia vera and in about half of the patients with essential thrombocythemia or myelofibrosis,1–4 has been found in a high proportion of patients with Budd-Chiari syndrome (BCS)5 or in noncirrhotic patients with portal and mesenteric venous thrombosis, a heterogeneous group of disorders.6 We now report a new mutation in the JAK2 gene locus in 2 unrelated noncirrhotic patients with polycythemia vera and presenting with splanchnic venous thrombosis diagnosed and followed at the Gastroenterology Unit of the "A. Cardarelli" Hospital, Naples, Italy. Patients were a 39-year-old woman with portal and mesenteric venous thrombosis (Table 1, no. 1) and a 14-year-old girl with Budd-Chiari syndrome (Table 1, no. 2). Approval was obtained from the "A. Cardarelli" Hospital and the Scientific Institute for Research, Hospitalization, and Health Care (Istituto Cura a Carattere Scientifico [IRCCS]) "Casa Sollievo della Sofferenza" institutional review board for these studies. Informed consent was obtained in accordance with the Declaration of Helsinki. Venous thromboses were diagnosed by Doppler ultrasonography, spiral computed tomography, or magnetic resonance imaging as required during the routine diagnostic work-up. Polycythemia vera was diagnosed according to established criteria.7 DNA was extracted from peripheral blood leukocytes according to standard protocols, and amplifications of all coding regions of the JAK2 gene and intron/exon boundaries were achieved using sense and antisense oligonucleotides designed and numbered on the basis of the known sequence of the JAK2 gene locus (GenBank accession no. AL161450). Then, amplified DNA fragments were subjected to direct cycle-sequence analysis using an ABI PRISM 3100 Genetic Analyzer sequencer (PE Biosystems, Foster City, CA). Gene sequencing of the JAK2 gene locus showed a heterozygous GAAATG deletion in exon 12 at DNA position 51324–51329 (numbered according to GenBank accession no. AL161450), leading to an ArgLys (AGA>AAA) substitution at amino acid position 541 and Asn (542)–Glu (543) deletion (Figure 1). The deletion abolishes a site of action for the MboII endonuclease (Figure 1). No other acquired or genetic thrombophilic risk factor or cytogenetic abnormality was identified in either patient. The currently reported mutation is similar to one previously described (ie, N542-E543del),8 and molecular modeling suggested that residues 541 through 543 lie within a region linking the predicted SH2 and JH2 domains of JAK2.9 Although it is unclear how the present mutation and others occurring in exon 12 may affect JAK2 functioning, the Asn (542)–Glu (543) deletion has been shown as a gain-of-function mutation leading to ligand-independent signaling through JAK2.8 View this table: [in this window] [in a new window]   Table 1. Clinical and bone marrow histologic data   View larger version (58K): [in this window] [in a new window]   Figure 1. Sequence traces and restriction enzyme-based assessment of the new JAK2 mutation. (A) Electropherogram showing the c.51324–51329 deletion in exon 12 of the JAK2 gene. The arrows indicate the position of deleted nucleotides. (B) DNA gel electrophoresis DNA of exon 12 including the deletion before (lanes 1, 3, and 5) and after (lanes 2, 4, and 6) digestion with MboII, derived from patients (lanes 1 trough 4) and control (lanes 5 and 6). MW indicates 50-bp ladder DNA molecular-weight markers; and *, the 195-bp fragment containing the deletion and lacking of a MboII site, which substitutes for 115-bp and 86-bp fragments (arrows).   In V617F-negative patients with a myeloproliferative disorder and a normal karyotype, acquired somatic mutations have been found in exon 12,9 suggesting that this region may be a "hot-spot" for gain-of-function mutations. Because a portion of patients presenting with splanchnic venous thrombosis did not suffer from an overt myeloproliferative disorder,6 present findings suggest that, in addition to JAK2 V617F, screening for exon 12 mutations may be useful to recognize patients who should be carefully observed for the subsequent development of overt disease. Authorship Correspondence: Maurizio Margaglione, Cattedra di Genetica Medica, Dipartimento di Scienze Biomediche, Università degli Studi di Foggia, viale Pinto, Foggia 71100, Italy; e-mail: m.margaglione{at}unifg.it. Conflict-of-interest disclosure: The authors declare no competing financial interests. Donatella Colaizzo, Lucio Amitrano, Giovanni L. Tiscia, Elvira Grandone, Maria Anna Guardascione, and Maurizio Margaglione References James C, Ugo V, Le Couedic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434:1144–1148.[CrossRef][Medline] [Order article via Infotrieve] Kralovics R, Teo SS, Buser AS, et al. Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of Jak2. Blood 2005; 106:3374–3376.[Abstract/Free Full Text] Levine RL, Loriaux M, Huntly BJ, et al. 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; 106:3377–3379.[Abstract/Free Full Text] Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005; 7:387–397.[CrossRef][Medline] [Order article via Infotrieve] Patel RK, Lea NC, Heneghan MA, et al. Prevalence of the activating JAK2 tyrosine kinase mutation V617F in the Budd-Chiari syndrome. Gastroenterology 2006; 130:2031–2038.[CrossRef][Medline] [Order article via Infotrieve] Colaizzo D, Amitrano L, Tiscia GL, et al. The JAK2 V617F mutation frequently occurs in patients with portal and mesenteric venous thrombosis. J Thromb Haemost 2007; 5:55–61.[CrossRef][Medline] [Order article via Infotrieve] Pierre R, Thiele J, Vardiman J W, Brunning R D, Flandrin G. Pathology and genetics of tumors of haematopoietic and lymphoid tissues. In Jaffe ES, Harris NL, Stein H, Vardiman JW (Eds.). The World Health Organization Classification of Tumors2001;Lyon, France IARC Press pp. 32–44. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007; 356:459–468.[Abstract/Free Full Text] Giordanetto F and Kroemer RT. Prediction of the structure of human Janus kinase 2 (JAK2) comprising JAK homology domains 1 through 7. Protein Eng 2002; 15:727–737.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J.-J. Kiladjian, F. Cervantes, F. W. G. Leebeek, C. Marzac, B. Cassinat, S. Chevret, D. Cazals-Hatem, A. Plessier, J.-C. Garcia-Pagan, S. D. Murad, et al. The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases Blood, May 15, 2008; 111(10): 4922 - 4929. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Colaizzo, D. Articles by Margaglione, M. Search for Related Content PubMed PubMed Citation Articles by Colaizzo, D. Articles by Margaglione, M. Social Bookmarking                   What's this?

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