Titre Du Document

Titre du document / Document title JAK2 V617F in myeloid disorders : What do we know now, and where are we headed? Auteur(s) / Author(s) NELSON Maria E. ; STEENSMA David P. ; Résumé / Abstract Activating tyrosine kinase (TK) mutations disrupt cellular proliferation and survival pathways and are increasingly recognized as a fundamental cause of human cancers. Until very recently, the only TK mutations widely observed in myeloid neoplasia were the BCR/ABL1 fusions characteristic of chronic myeloid leukemia and some acute leukemias, and FLT3 activating mutations in a minority of acute myeloid leukemias. Several rare TK mutations are found in various atypical myeloproliferative disorders, but big pieces of the pathobiological puzzle were glaringly missing. In the first half of 2005, one gap was filled in: 7 studies identified the same acquired amino acid substitution (V617F) in the Janus kinase 2 (JAK2) TK in large numbers of patients with diverse clonal myeloid disorders. Most affected patients suffer from the classic BCR/ABL1-negative myeloproliferative disorders (MPD), especially polycythemia vera (74% of n = 506), but a subset of people with essential thrombocythemia (36% of n = 339) or myelofibrosis with myeloid metaplasia (44% of n = 127) bear the identical mutation, as do a few individuals with myelodysplastic syndromes or an atypical myeloid disorder (7% of n = 556). This long-sought common mutation in BCR/ABL1-negative MPD raises many provocative biological and clinical questions, and demands reevaluation of prevailing diagnostic algorithms for erythrocytosis and thrombocytosis. JAK2 V617F may provide novel molecular targets for drug therapy, and suggests other places to seek cooperating mutations or mutations associated with similar phenotypes. The story of this exciting finding will unfold rapidly in the years ahead, and ongoing developments will be important for all hematologists to understand. Revue / Journal Title Leukemia & lymphoma ISSN 1042-8194 Source / Source 2006, vol. 47, no2, pp. 177-194 [18 page(s) (article)] Langue / Language Anglais Editeur / Publisher Taylor & Francis, Abingdon, ROYAUME-UNI (1989) (Revue) Mots-clés d'auteur / Author Keywords Janus kinase 2 ; myeloproliferative disorders ; polycythemia vera ; essential thrombocythemia ; myelofibrosis with myeloid metaplasia ; molecular genetics ; tyrosine kinase ; atypical myeloproliferative disorders ; myelodysplastic syndromes ; Localisation / Location INIST-CNRS, Cote INIST : 26108, 35400013533642.0010

• From American Journal of Clinical Pathology

JAK2 V617F Mutation in Patients With Catastrophic Intraabdominal Thromboses Posted 05/25/2007

Christine McMahon, MD; Kareem Abu-Elmagd, MD, PhD; Franklin A. Bontempo, MD; Jeffrey A. Kant, MD, PhD; Steven H. Swerdlow, MD Author Information INFORMATION FROM INDUSTRY Assess clinically focused product information on Medscape. Click Here for Product Infosites – Information from Industry.

Abstract and Introduction Abstract

Catastrophic intra-abdominal thrombosis can result from a variety of prothrombotic states, including polycythemia vera and essential thrombocythemia, both of which are frequently associated with an acquired mutation (V617F) in the JAK2 gene. To assess the prevalence and clinical implications of this mutation in the setting of intra-abdominal thrombosis, JAK2 V617F genotyping was performed in 42 patients who had catastrophic intra-abdominal thromboses resulting in visceral transplants. The prevalence of V617F was compared with that of other prothrombotic states for which molecular testing is routinely performed. V617F mutations were detected in 7 patients (17%), who were not distinguishable on the basis of their peripheral blood cell counts. The median posttransplantation survival of V617F+ patients was 17.5 months, compared with 116.4 months for the V617F– patients (ratio, 6.6; 95% confidence interval, 6.37.0). These results highlight the diagnostic usefulness of JAK2 V617F testing in this setting and underscore the clinical significance of a positive result. Introduction

Chronic myeloproliferative disorders (CMPDs) and a number of other prothrombotic states confer an increased risk of visceral vascular thrombosis.[1-3] Polycythemia vera (PV) or essential thrombocythemia (ET) has been reported in 25% to 65% of patients with splanchnic vein thrombosis[4] and in up to 80% of patients with hepatic vein thrombosis (Budd-Chiari syndrome).[5,6] The clinical diagnosis of CMPD in the setting of intra-abdominal thrombosis can be obscured by the fact that hemoglobin levels, hematocrit values, leukocyte counts, and platelet counts may be only modestly elevated, within the normal range, or even decreased,[4,6-11] and erythropoietin levels may be normal or elevated.[12] Splenomegaly may not be present or may be attributed to congestion caused by portal hypertension. A recently described somatic mutation in the gene encoding a growth factor receptor–associated tyrosine kinase, JAK2, is present in myeloid cells of the majority of patients with PV and approximately one third of patients with ET or chronic idiopathic myelofibrosis.[13-19] This mutation results in the substitution of phenylalanine for an evolutionarily conserved valine residue (V617F) in the auto-inhibitory domain of JAK2 and thereby renders the kinase active even in the absence of growth factors. Given the notorious difficulty sometimes encountered in recognizing CMPDs in patients with intraabdominal thromboses, molecular testing for the JAK2 V617F mutation may be of particular interest in this setting. Visceral vascular thrombosis is a common cause of native intestinal loss in patients who are referred for intestinal transplants.[20] We, therefore, studied the prevalence of the JAK2 V617F mutation in patients who had intra-abdominal thromboses that resulted in the need for small intestinal or multivisceral transplantation, the majority of whom did not have a clinically recognized CMPD. The incidence was compared with that of other prothrombotic risk factors in these patients, and the clinical implications of finding the JAK2 V617F mutation were evaluated. Section 1 of 4 Next Page: Materials and Methods •

Printer- Friendly

• 1. 2.

Email This

Menon KVN, Shah V, Kamath P. The Budd-Chiari syndrome. N Engl J Med. 2004;350:578-585. Kumar S, Sarr MG, Kamath P. Mesenteric venous thrombosis. N Engl J Med. 2001;345:1683-1688. 3. Briere J. Budd-Chiari syndrome and portal vein thrombosis associated with myeloproliferative disorders: diagnosis and management. Semin Thromb Hemost. 2006;32:208-218.

4.

Chait Y, Condat B, Cazals-Hatem D, et al. Relevance of the criteria commonly used to diagnose myeloproliferative disorder in patients with splanchnic vein thrombosis. Br J Haematol. 2005;129:553-560. 5. Melear JM, Goldstein RM, Levy MF, et al. Hematologic aspects of liver transplantation for BuddChiari syndrome with special reference to myeloproliferative disorders. Transplantation. 2002;74:1090-1095. 6. Valla D, Casadevall N, Lacombe C, et al. Primary myeloproliferative disorder and hepatic vein thrombosis: a prospective study of erythroid colony formation in vitro in 20 patients with Budd-Chiari syndrome. Ann Intern Med. 1985;103:329-334. 7. Anger BR, Seifried E, Scheppach J, et al. Budd-Chiari syndrome and thrombosis of other abdominal vessels in the chronic myeloproliferative diseases. Klin Wochenschr. 1989;67:818-825. 8. Regev A, Stark P, Blickstein D, et al. Thrombotic complications of essential thrombocythemia with relatively low platelet counts. Am J Hematol. 1997;56:168-172. 9. De Stefano V, Teofili L, Leone G, et al. Spontaneous erythroid colony formation as the clue to an underlying myeloproliferative disorder in patients with Budd-Chiari syndrome or portal vein thrombosis. Semin Thromb Hemost. 1997;23:411-418. 10. McNamara C, Juneja S, Wolf M, et al. Portal or hepatic vein thrombosis as the first presentation of a myeloproliferative disorder in patients with normal peripheral blood counts. Clin Lab Haematol. 2002;24:239-242. 11. 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. 12. Thurmes PJ, Steensma DP. Elevated serum erythropoietin levels in patients with Budd-Chiari syndrome secondary to polycythemia vera: clinical implications for the role of JAK2 mutation analysis. Eur J Haematol. 2006;77:57-60. 13. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054-1061. 14. 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. 15. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779-1790. 16. 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. 17. Jones AV, Kreil S, Zoi K, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood. 2005;106:2162-2168. 18. Zhao R, Xing S, Li Z, et al. Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem. 2005;280:22788-22792. 19. Jelinek J, Oki Y, Gharibyan V, et al. JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome–negative CML, and megakaryocytic leukemia. Blood. 2005;106:3370-3373. 20. Giraldo M, Martin D, Colangelo J, et al. Intestinal transplantation for patients with short gut syndrome and hypercoagulable states. Transplant Proc. 2000;32:1223-1224. 21. Ridker PM, Miletich JP, Hennekens CH, et al. Ethnic distributions of factor V Leiden in 4047 men and women: implications for venous thromboembolism screening. JAMA. 1997;277:1305-1307. 22. Poort SR, Rosendaal FR, Reitsma PH, et al. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88:3698-3703. 23. Greiner TC. Diagnostic assays for the JAK2 V617F mutation in chronic myeloproliferative disorders. Am J Clin Pathol. 2006;125:651-653. 24. Sidon P, Heimann P, Lambert F, et al. Combined locked nucleic acid and molecular beacon technologies for sensitive detection of the JAK2V617F somatic single-base sequence variant. Clin Chem. 2006;52:1436-1438. 25. Sidon P, El Housni H, Dessars B, et al. The JAK2V617F mutation is detectable at very low level in peripheral blood of healthy donors [letter]. Leukemia. 2006;20:1622. 26. Falanga A, Marchetti M, Evangelista V, et al. Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood. 2000;96:4261-4266. 27. Falanga A, Marchetti M, Vignoli A, et al. Leukocyte-platelet interaction in patients with essential

thrombocythemia and polycythemia vera. Exp Hematol. 2005;33:523-530.

28. Arellano-Rodrigo E, Alvarez-Larran A, Reverter JC, et al. Increased platelet and leukocyte activation as contributing mechanisms for thrombosis in essential thrombocythemia and correlation with the JAK2 mutational status. Haematologica. 2006;91:169-175. 29. Alvarez-Larran A, Garcia-Pagan JC, Abraldes JG, et al. Increased CD11b neutrophil expression in Budd-Chiari syndrome or portal vein thrombosis secondary to polycythemia vera. Br J Haematol. 2004;124:329-335. 30. Harrison CN. Platelets and thrombosis in myeloproliferative diseases. Hematology (Am Soc Hematol Educ Program). 2005:409-415. 31. Falanga A, Marchetti M, Barbui T, et al. Pathogenesis of thrombosis in essential thrombocythemia and polycythemia vera: the role of neutrophils. Semin Hematol. 2005;42:239-247. 32. Valla D, Casadevall N, Huisse MG, et al. Etiology of portal vein thrombosis in adults: a prospective evaluation of primary myeloproliferative disorders. Gastroenterology. 1988;94:1063-1069. 33. Denninger MH, Chait Y, Casadevall N, et al. Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors. Hepatology. 2000;31:587-591.

Am J Clin Pathol. 2007;127(5):736-743. ©2007 American Society for Clinical Pathology

• • •

Printer-Friendly

• •

Email This Discuss This

From American Journal of Clinical Pathology

JAK2 V617F Mutation in Patients With Catastrophic Intraabdominal Thromboses Posted 05/25/2007

Christine McMahon, MD; Kareem Abu-Elmagd, MD, PhD; Franklin A. Bontempo, MD; Jeffrey A. Kant, MD, PhD; Steven H. Swerdlow, MD Author Information INFORMATION FROM INDUSTRY Assess clinically focused product information on Medscape. Click Here for Product Infosites – Information from Industry.

Abstract and Introduction Abstract

Catastrophic intra-abdominal thrombosis can result from a variety of prothrombotic states, including polycythemia vera and essential thrombocythemia, both of which are frequently associated with an acquired mutation (V617F) in the JAK2 gene. To assess the prevalence and clinical implications of this mutation in the setting of intra-abdominal thrombosis, JAK2 V617F genotyping was performed in 42 patients who had catastrophic intra-abdominal thromboses resulting in visceral transplants. The prevalence of V617F was compared with that of other prothrombotic states for which molecular testing is routinely performed. V617F mutations were detected in 7 patients (17%), who were not distinguishable on the basis of their peripheral blood cell counts. The median posttransplantation survival of V617F+ patients was 17.5 months, compared with 116.4 months for the V617F– patients (ratio, 6.6; 95% confidence interval, 6.37.0). These results highlight the diagnostic usefulness of JAK2 V617F testing in this setting and underscore the clinical significance of a positive result.

Introduction

Chronic myeloproliferative disorders (CMPDs) and a number of other prothrombotic states confer an increased risk of visceral vascular thrombosis.[1-3] Polycythemia vera (PV) or essential thrombocythemia (ET) has been reported in 25% to 65% of patients with splanchnic vein thrombosis[4] and in up to 80% of patients with hepatic vein thrombosis (Budd-Chiari syndrome).[5,6] The clinical diagnosis of CMPD in the setting of intra-abdominal thrombosis can be obscured by the fact that hemoglobin levels, hematocrit values, leukocyte counts, and platelet counts may be only modestly elevated, within the normal range, or even decreased,[4,6-11] and erythropoietin levels may be normal or elevated.[12] Splenomegaly may not be present or may be attributed to congestion caused by portal hypertension. A recently described somatic mutation in the gene encoding a growth factor receptor–associated tyrosine kinase, JAK2, is present in myeloid cells of the majority of patients with PV and approximately one third of patients with ET or chronic idiopathic myelofibrosis.[13-19] This mutation results in the substitution of phenylalanine for an evolutionarily conserved valine residue (V617F) in the auto-inhibitory domain of JAK2 and thereby renders the kinase active even in the absence of growth factors. Given the notorious difficulty sometimes encountered in recognizing CMPDs in patients with intraabdominal thromboses, molecular testing for the JAK2 V617F mutation may be of particular interest in this setting. Visceral vascular thrombosis is a common cause of native intestinal loss in patients who are referred for intestinal transplants.[20] We, therefore, studied the prevalence of the JAK2 V617F mutation in patients who had intra-abdominal thromboses that resulted in the need for small intestinal or multivisceral transplantation, the majority of whom did not have a clinically recognized CMPD. The incidence was compared with that of other prothrombotic risk factors in these patients, and the clinical implications of finding the JAK2 V617F mutation were evaluated. Section 1 of 4 Next Page: Materials and Methods •

Printer- Friendly

• 1.

Email This

Menon KVN, Shah V, Kamath P. The Budd-Chiari syndrome. N Engl J Med. 2004;350:578-585. Kumar S, Sarr MG, Kamath P. Mesenteric venous thrombosis. N Engl J Med. 2001;345:1683-1688. 3. Briere J. Budd-Chiari syndrome and portal vein thrombosis associated with myeloproliferative disorders: diagnosis and management. Semin Thromb Hemost. 2006;32:208-218. 4. Chait Y, Condat B, Cazals-Hatem D, et al. Relevance of the criteria commonly used to diagnose myeloproliferative disorder in patients with splanchnic vein thrombosis. Br J Haematol. 2005;129:553-560. 5. Melear JM, Goldstein RM, Levy MF, et al. Hematologic aspects of liver transplantation for BuddChiari syndrome with special reference to myeloproliferative disorders. Transplantation. 2002;74:1090-1095. 6. Valla D, Casadevall N, Lacombe C, et al. Primary myeloproliferative disorder and hepatic vein thrombosis: a prospective study of erythroid colony formation in vitro in 20 patients with Budd-Chiari syndrome. Ann Intern Med. 1985;103:329-334. 7. Anger BR, Seifried E, Scheppach J, et al. Budd-Chiari syndrome and thrombosis of other abdominal vessels in the chronic myeloproliferative diseases. Klin Wochenschr. 1989;67:818-825. 8. Regev A, Stark P, Blickstein D, et al. Thrombotic complications of essential thrombocythemia with relatively low platelet counts. Am J Hematol. 1997;56:168-172. 9. De Stefano V, Teofili L, Leone G, et al. Spontaneous erythroid colony formation as the clue to an underlying myeloproliferative disorder in patients with Budd-Chiari syndrome or portal vein thrombosis. Semin Thromb Hemost. 1997;23:411-418. 10. McNamara C, Juneja S, Wolf M, et al. Portal or hepatic vein thrombosis as the first presentation of a 2.

myeloproliferative disorder in patients with normal peripheral blood counts. Clin Lab Haematol. 2002;24:239-242. 11. 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. 12. Thurmes PJ, Steensma DP. Elevated serum erythropoietin levels in patients with Budd-Chiari syndrome secondary to polycythemia vera: clinical implications for the role of JAK2 mutation analysis. Eur J Haematol. 2006;77:57-60. 13. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054-1061. 14. 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. 15. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779-1790. 16. 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. 17. Jones AV, Kreil S, Zoi K, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood. 2005;106:2162-2168. 18. Zhao R, Xing S, Li Z, et al. Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem. 2005;280:22788-22792. 19. Jelinek J, Oki Y, Gharibyan V, et al. JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome–negative CML, and megakaryocytic leukemia. Blood. 2005;106:3370-3373. 20. Giraldo M, Martin D, Colangelo J, et al. Intestinal transplantation for patients with short gut syndrome and hypercoagulable states. Transplant Proc. 2000;32:1223-1224. 21. Ridker PM, Miletich JP, Hennekens CH, et al. Ethnic distributions of factor V Leiden in 4047 men and women: implications for venous thromboembolism screening. JAMA. 1997;277:1305-1307. 22. Poort SR, Rosendaal FR, Reitsma PH, et al. A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996;88:3698-3703. 23. Greiner TC. Diagnostic assays for the JAK2 V617F mutation in chronic myeloproliferative disorders. Am J Clin Pathol. 2006;125:651-653. 24. Sidon P, Heimann P, Lambert F, et al. Combined locked nucleic acid and molecular beacon technologies for sensitive detection of the JAK2V617F somatic single-base sequence variant. Clin Chem. 2006;52:1436-1438. 25. Sidon P, El Housni H, Dessars B, et al. The JAK2V617F mutation is detectable at very low level in peripheral blood of healthy donors [letter]. Leukemia. 2006;20:1622. 26. Falanga A, Marchetti M, Evangelista V, et al. Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood. 2000;96:4261-4266. 27. Falanga A, Marchetti M, Vignoli A, et al. Leukocyte-platelet interaction in patients with essential thrombocythemia and polycythemia vera. Exp Hematol. 2005;33:523-530. 28. Arellano-Rodrigo E, Alvarez-Larran A, Reverter JC, et al. Increased platelet and leukocyte activation as contributing mechanisms for thrombosis in essential thrombocythemia and correlation with the JAK2 mutational status. Haematologica. 2006;91:169-175. 29. Alvarez-Larran A, Garcia-Pagan JC, Abraldes JG, et al. Increased CD11b neutrophil expression in Budd-Chiari syndrome or portal vein thrombosis secondary to polycythemia vera. Br J Haematol. 2004;124:329-335. 30. Harrison CN. Platelets and thrombosis in myeloproliferative diseases. Hematology (Am Soc Hematol Educ Program). 2005:409-415. 31. Falanga A, Marchetti M, Barbui T, et al. Pathogenesis of thrombosis in essential thrombocythemia and polycythemia vera: the role of neutrophils. Semin Hematol. 2005;42:239-247. 32. Valla D, Casadevall N, Huisse MG, et al. Etiology of portal vein thrombosis in adults: a prospective evaluation of primary myeloproliferative disorders. Gastroenterology. 1988;94:1063-1069. 33. Denninger MH, Chait Y, Casadevall N, et al. Cause of portal or hepatic venous thrombosis in adults: the role of multiple concurrent factors. Hepatology. 2000;31:587-591.

Am J Clin Pathol. 2007;127(5):736-743. ©2007 American Society for Clinical Pathology