New Insights into the Pathogenesis of JAK2 V617F-Positive Myeloproliferative Disorders and Consequences for the Management of Patients

ABSTRACT

The identification of the JAK2 V617F mutation in patients with myeloproliferative disorders (MPDs) represents a major breakthrough in our understanding of the pathogenesis of these diseases. One year after its discovery, an impressive number of publications appeared. These articles confirmed most of the initial results and tried to focus on the main issues arising from this discovery. JAK2 V617F came as recognition of the work of many investigators, starting with William Dameshek, who demonstrated that classical MPDs shared phenotypical mimicry and a general pattern of clinical evolution. We now know that this mutation is the common mark of a molecular clinical entity of MPD shared by 90% of polycythemia vera (PV) and ~50% of essential thrombocythemia and idiopathic myelofibrosis patients. However, many questions arise from this discovery. This review, in view of the recent literature, tries to address crucial questions regarding the mechanism of action and the clinical relevance of the JAK2 V617F mutation. The first question is how a unique mutation may explain the clinical diversity of JAK2 V617F-positive MPDs. We now know that acquisition of this mutation is only one step, and that gain of the JAK2 V617F locus, as gain in constitutive Janus kinase 2 (JAK2) activity, may represent another step in disease progression. It is still not known if and how this event or other unknown events may favor disease diversity and possibly disease onset. The second question is how the identification of the JAK2 V617F mutation will change our approach to patients. If detection of JAK2 V617F drastically simplifies the diagnosis of MPDs, and especially PV, prospective clinical trials will be necessary to determine if the therapeutic attitude and disease prognosis will depend on the presence of JAK2 V617F. The third question is how this discovery will benefit the patients. The immediate benefits are still difficult to evaluate, but this discovery, as a major advance in our understanding of the pathogenesis of MPDs, surely has opened perspectives for possible targeted therapies and raises new hopes for patients and clinicians.

KEYWORDS

Myeloproliferative disorders - JAK2 V617F - diversity - diagnosis - prognosis - treatment

REFERENCES

• 1 Dameshek W. Some speculations on the myeloproliferative syndromes.  Blood. 1951;  6 372-375
• 2 Spivak J L. The chronic myeloproliferative disorders: clonality and clinical heterogeneity.  Semin Hematol. 2004;  41 1-5
• 3 James C, Ugo V, Casadevall N, Constantinescu S N, Vainchenker W. A JAK2 mutation in myeloproliferative disorders: pathogenesis and therapeutic and scientific prospects.  Trends Mol Med. 2005;  11 548-554
• 4 Vardiman J W, Harris N L, Brunning R D. The world health organization (WHO) classification of the myeloid neoplasms.  Blood. 2002;  100 2292-2302
• 5 Adamson J W, Fialkow P J, Murphy S, Prchal J F, Steinmann L. Polycythemia vera: stem-cell and probable clonal origin of the disease.  N Engl J Med. 1976;  295 913-916
• 6 Fialkow P J, Faguet G B, Jacobson R J, Vaidya K, Murphy S. Evidence that essential thrombocythemia is a clonal disorder with origin in a multipotent stem cell.  Blood. 1981;  58 916-919
• 7 el-Kassar N, Hetet G, Briere J, Grandchamp B. Clonality analysis of hematopoiesis in essential thrombocythemia: advantages of studying T lymphocytes and platelets.  Blood. 1997;  89 128-134
• 8 Harrison C N, Gale R E, Machin S J, Linch D C. A large proportion of patients with a diagnosis of essential thrombocythemia do not have a clonal disorder and may be at lower risk of thrombotic complications.  Blood. 1999;  93 417-424
• 9 Prchal J F, Axelrad A A. Letter: bone-marrow responses in polycythemia vera.  N Engl J Med. 1974;  290 1382
• 10 Pahl H L. PRV-1 mRNA expression and other molecular markers in polycythemia rubra vera.  Curr Hematol Rep. 2003;  2 231-236
• 11 Moliterno A R, Hankins W D, Spivak J L. Impaired expression of the thrombopoietin receptor by platelets from patients with polycythemia vera.  N Engl J Med. 1998;  338 572-580
• 12 Ugo V, Marzac C, Teyssandier I et al.. Multiple signaling pathways are involved in erythropoietin-independent differentiation of erythroid progenitors in polycythemia vera.  Exp Hematol. 2004;  32 179-187
• 13 James C, Ugo V, Le Couedic J P et al.. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.  Nature. 2005;  434 1144-1148
• 14 Kralovics R, Passamonti F, Buser A S et al.. A gain-of-function mutation of JAK2 in myeloproliferative disorders.  N Engl J Med. 2005;  352 1779-1790
• 15 Baxter E J, Scott L M, Campbell P J et al.. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.  Lancet. 2005;  365 1054-1061
• 16 Levine R L, 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 Zhao R, Xing S, Li Z et al.. Identification of an acquired JAK2 mutation in polycythemia vera.  J Biol Chem. 2005;  280 22788-22792
• 18 Frohling S, Scholl C, Gilliland D G, Levine R L. Genetics of myeloid malignancies: pathogenetic and clinical implications.  J Clin Oncol. 2005;  23 6285-6295
• 19 De Keersmaecker K, Cools J. Chronic myeloproliferative disorders: a tyrosine kinase tale.  Leukemia. 2006;  20 200-205
• 20 Saharinen P, Vihinen M, Silvennoinen O. Autoinhibition of JAK2 tyrosine kinase is dependent on specific regions in its pseudokinase domain.  Mol Biol Cell. 2003;  14 1448-1459
• 21 Schindler C W. Series introduction. JAK-STAT signaling in human disease.  J Clin Invest. 2002;  109 1133-1137
• 22 Wernig G, Mercher T, Okabe R, Levine R L, Lee B H, Gilliland D G. Expression of JAK2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model.  Blood. 2006;  107 4274-4281
• 23 Lu X, Levine R, Tong W et al.. Expression of a homodimeric type I cytokine receptor is required for JAK2V617F-mediated transformation.  Proc Natl Acad Sci USA. 2005;  102 18962-18967
• 24 Staerk J, Kallin A, Demoulin J B, Vainchenker W, Constantinescu S N. JAK1 and TYK2 activation by the homologous polycythemia vera JAK2 V617F mutation: Cross-talk with igf1 receptor.  J Biol Chem. 2005;  280 41893-41899
• 25 Villeval J L, Cohen-Solal K, Tulliez M et al.. High thrombopoietin production by hematopoietic cells induces a fatal myeloproliferative syndrome in mice.  Blood. 1997;  90 4369-4383
• 26 Tefferi A, Lasho T L, Gilliland G. JAK2 mutations in myeloproliferative disorders.  N Engl J Med. 2005;  353 1416-1417
• 26a Lacout C, Pisani D F, Tulliez M et al.. JAK2 V617F expression in mrine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis.  Blood. 2006 May 2;  , [Epub ahead of print]
• 27 Spivak J L. Diagnosis of the myeloproliferative disorders: resolving phenotypic mimicry.  Semin Hematol. 2003;  40 1-5
• 28 Kaushansky K. On the molecular origins of the chronic myeloproliferative disorders: it all makes sense.  Hematology (Am Soc Hematol Educ Program). 2005;  533-537
• 29 Antonioli E, Guglielmelli P, Pancrazzi A et al.. Clinical implications of the JAK2 V617F mutation in essential thrombocythemia.  Leukemia. 2005;  19 1847-1849
• 30 Levine R L, Belisle C, Wadleigh M et al.. X-inactivation based clonality analysis and quantitative JAK2V617F assessment reveals a strong association between clonality and JAK2V617F in pv but not et/mmm, and identifies a subset of JAK2V617F negative et and mmm patients with clonal hematopoiesis.  Blood. 2006;  , In press
• 31 Tefferi A, Pardanani A. Mutation screening for JAK2(V617F): when to order the test and how to interpret the results.  Leuk Res. 2006;  , In press
• 32 Campbell P J, Scott L M, Buck G et al.. Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study.  Lancet. 2005;  366 1945-1953
• 33 Tefferi A, Lasho T L, Schwager S M et al.. The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera.  Cancer. 2006;  106 631-635
• 34 Passamonti F, Rumi E, Pietra D et al.. Relation between JAK2 (V617F) mutation status, granulocyte activation and constitutive mobilization of cd34-positive cells into peripheral blood in myeloproliferative disorders.  Blood. 2005;  , In press
• 35 Zhao Z J, Vainchenker W, Krantz S B, Casadevall N, Constantinescu S N. Role of tyrosine kinases and phosphatases in polycythemia vera.  Semin Hematol. 2005;  42 221-229
• 36 Wormald S, Hilton D J. Inhibitors of cytokine signal transduction.  J Biol Chem. 2004;  279 821-824
• 37 Moliterno A R, Williams D M, Gutierrez-Alamillo L I, Salvatori R, Ingersoll R G, Spivak J L. Mpl Baltimore: a thrombopoietin receptor polymorphism associated with thrombocytosis.  Proc Natl Acad Sci USA. 2004;  101 11444-11447
• 38 Huang L J, Constantinescu S N, Lodish H F. The n-terminal domain of janus kinase 2 is required for golgi processing and cell surface expression of erythropoietin receptor.  Mol Cell. 2001;  8 1327-1338
• 39 Royer Y, Staerk J, Costuleanu M, Courtoy P J, Constantinescu S N. Janus kinases affect thrombopoietin receptor cell surface localization and stability.  J Biol Chem. 2005;  280 27251-27261
• 40 Arellano-Rodrigo E, Alvarez-Larran A, Reverter J C, Villamor N, Colomer D, Cervantes F. 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
• 41 Campbell P J, Griesshammer M, Dohner K et al.. V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofibrosis.  Blood. 2006;  107 2098-2100
• 42 Bench A J, Pahl H L. Chromosomal abnormalities and molecular markers in myeloproliferative disorders.  Semin Hematol. 2005;  42 196-205
• 43 Skoda R, Prchal J T. Lessons from familial myeloproliferative disorders.  Semin Hematol. 2005;  42 266-273
• 43a Bellanné-Chantelot C, Chaumarel I, Labopin M et al.. Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders.  Blood. 2006 Mar 14;  , [Epub ahead of print]
• 44 James C, Delhommeau F, Marzac C et al.. Detection of JAK2 V617F as a first intention diagnostic test for erythrocytosis.  Leukemia. 2006;  20 350-353
• 45 Jones A V, Kreil S, Zoi K et al.. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders.  Blood. 2005;  106 2162-2168
• 46 Campbell P J, Scott L M, Baxter E J, Bench A J, Green A R, Erber W N. Methods for the detection of the JAK2 V617F mutation in human myeloproliferative disorders.  Methods Mol Med. 2006;  125 253-264
• 47 Michiels J J, Thiele J. Clinical and pathological criteria for the diagnosis of essential thrombocythemia, polycythemia vera, and idiopathic myelofibrosis (agnogenic myeloid metaplasia).  Int J Hematol. 2002;  76 133-145
• 48 Thiele J, Kvasnicka H M, Orazi A. Bone marrow histopathology in myeloproliferative disorders-current diagnostic approach.  Semin Hematol. 2005;  42 184-195
• 49 Thiele J, Kvasnicka H M. A critical reappraisal of the who classification of the chronic myeloproliferative disorders.  Leuk Lymphoma. 2006;  47 381-396
• 50 Goerttler P S, Steimle C, Marz E et al.. The JAK2V617F mutation, prv-1 overexpression, and eec formation define a similar cohort of mpd patients.  Blood. 2005;  106 2862-2864
• 51 Bellosillo B, Besses C, Florensa L, Sole F, Serrano S. JAK2 V617F mutation, prv-1 overexpression and endogenous erythroid colony formation show different coexpression patterns among ph-negative chronic myeloproliferative disorders.  Leukemia. 2006;  20 736
• 52 Tefferi A, Sirhan S, Lasho T L et al.. Concomitant neutrophil JAK2 mutation screening and prv-1 expression analysis in myeloproliferative disorders and secondary polycythaemia.  Br J Haematol. 2005;  131 166-171
• 53 Goerttler P S, Kreutz C, Donauer J et al.. Gene expression profiling in polycythaemia vera: overexpression of transcription factor nf-e2.  Br J Haematol. 2005;  129 138-150
• 54 Kralovics R, Teo S S, Buser A S et al.. Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of JAK2.  Blood. 2005;  106 3374-3376
• 55 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
• 56 Wolanskyj A P, Lasho T L, Schwager S M et al.. JAK2 mutation in essential thrombocythaemia: clinical associations and long-term prognostic relevance.  Br J Haematol. 2005;  131 208-213
• 57 Krause D S, Van Etten R A. Tyrosine kinases as targets for cancer therapy.  N Engl J Med. 2005;  353 172-187
• 58 Jones A V, Silver R T, Waghorn K et al.. Minimal molecular response in polycythemia vera patients treated with imatinib or interferon alpha.  Blood. 2005;  , In press
• 59 Lucet I S, Fantino E, Styles M et al.. The structural basis of janus kinase 2 inhibition by a potent and specific pan-janus kinase inhibitor.  Blood. 2006;  107 176-183
• 60 Lacronique V, Boureux A, Monni R et al.. Transforming properties of chimeric tel-jak proteins in ba/f3 cells.  Blood. 2000;  95 2076-2083
• 61 Sternberg D W, Gilliland D G. The role of signal transducer and activator of transcription factors in leukemogenesis.  J Clin Oncol. 2004;  22 361-371
• 62 Sandberg E M, Wallace T A, Godeny M D, Vonderlinden D, Sayeski P P. JAK2 tyrosine kinase: a true jak of all trades?.  Cell Biochem Biophys. 2004;  41 207-232
• 63 Wagner K U, Krempler A, Triplett A A et al.. Impaired alveologenesis and maintenance of secretory mammary epithelial cells in JAK2 conditional knockout mice.  Mol Cell Biol. 2004;  24 5510-5520
• 64 Parganas E, Wang D, Stravopodis D et al.. JAK2 is essential for signaling through a variety of cytokine receptors.  Cell. 1998;  93 385-395
• 65 Neubauer H, Cumano A, Muller M, Wu H, Huffstadt U, Pfeffer K. JAK2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis.  Cell. 1998;  93 397-409
• 66 Komura E, Chagraoui H, Mansat de Mas V et al.. Spontaneous STAT5 activation induces growth factor independence in idiopathic myelofibrosis: Possible relationship with fkbp51 overexpression.  Exp Hematol. 2003;  31 622-630
• 67 Tefferi A. Pathogenesis of myelofibrosis with myeloid metaplasia.  J Clin Oncol. 2005;  23 8520-8530