SEARCH:   Advanced

Blood, 15 November 2005, Vol. 106, No. 10, pp. 3370-3373. Prepublished online as a Blood First Edition Paper on July 21, 2005; DOI 10.1182/blood-2005-05-1800. This Article Abstract Full Text (PDF) All Versions of this Article: 2005-05-1800v1 106/10/3370    most recent 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 Jelinek, J. Articles by Issa, J.-P. J. Search for Related Content PubMed PubMed Citation Articles by Jelinek, J. Articles by Issa, J.-P. J. Related Collections Neoplasia Oncogenes and Tumor Suppressors Free Research Articles Brief Reports Clinical Trials and Observations Related Article in Blood Online Related Letter in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS Brief report JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome–negative CML, and megakaryocytic leukemia Jaroslav Jelinek, Yasuhiro Oki, Vazganush Gharibyan, Carlos Bueso-Ramos, Josef T. Prchal, Srdan Verstovsek, Miloslav Beran, Elihu Estey, Hagop M. Kantarjian, and Jean-Pierre J. Issa From the Departments of Leukemia and Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Baylor College of Medicine and Michael DeBakey Veterans Administration Hospital, Houston, TX; and the Department of Pathophysiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.    Abstract Top Abstract Introduction Study design Results and discussion References   An activating 1849G>T mutation of JAK2 (Janus kinase 2) tyrosine kinase was recently described in chronic myeloproliferative disorders (MPDs). Its role in other hematologic neoplasms is unclear. We developed a quantitative pyrosequencing assay and analyzed 374 samples of hematologic neoplasms. The mutation was frequent in polycythemia vera (PV) (86%) and myelofibrosis (95%) but less prevalent in acute myeloid leukemia (AML) with an antecedent PV or myelofibrosis (5 [36%] of 14 patients). JAK2 mutation was also detected in 3 (19%) of 16 patients with Philadelphia-chromosome (Ph)–negative chronic myelogenous leukemia (CML), 2 (18%) of 11 patients with megakaryocytic AML, 7 (13%) of 52 patients with chronic myelomonocytic leukemia, and 1 (1%) of 68 patients with myelodysplastic syndromes. No mutation was found in Ph+CML (99 patients), AML M0-M6 (28 patients), or acute lymphoblastic leukemia (20 patients). We conclude that the JAK2 1849G>T mutation is common in Ph– MPD but not critical for transformation to the acute phase of these diseases and that it is generally rare in aggressive leukemias.    Introduction Top Abstract Introduction Study design Results and discussion References   Janus kinase 2 (JAK2) is a tyrosine kinase involved in the transduction of cellular growth stimuli.1,2 Chromosomal translocations resulting in fusions deregulating JAK2 activity are implicated in leukemias.3-5 A somatic activating mutation, 1849G>T (Val617Phe), in the JAK2 gene was recently described in most patients with polycythemia vera (PV) and in approximately half those with essential thrombocythemia (ET) and myelofibrosis (MF).6-10 Mutation of both JAK2 alleles has been reported in approximately 30% of the patients.6-10 It has been proposed that wild-type JAK2 suppresses the transformation properties of mutant JAK2, providing a selective advantage to loss of heterozygosity at this locus.6 PV can progress to MF and to acute myelogenous leukemia (AML),11 and MF can also progress to AML.12 The role of JAK2 mutations in the transformation of myeloproliferative disorders to acute leukemia and in de novo acute leukemias, as well as in other hematologic malignancies, remains unclear. Infrequent occurrence of this unique JAK2 mutation has been reported recently in chronic myelomonocytic leukemia (CMML), atypical or unclassified myeloproliferative disorder (MPD), myelodysplastic syndrome (MDS), systemic mastocytosis, and chronic neutrophilic leukemia.13,14 Pyrosequencing is a rapid and quantitative technique suitable for detecting single nucleotide polymorphisms.15 We developed a pyrosequencing assay for the detection of the JAK2 1849G>T mutation in leukocyte genomic DNA and studied its prevalence in MPD and other hematologic malignancies.    Study design Top Abstract Introduction Study design Results and discussion References   Patient samples Samples were obtained from peripheral blood (n = 330) or bone marrow cells (n = 9) stored in a tissue bank in the Leukemia Department at M.D. Anderson Cancer Center and from Baylor College of Medicine. All patients gave consent for donation of samples to the tissue bank, in accordance with policies at the M.D. Anderson Cancer Center and Baylor College of Medicine. In 35 samples, DNA was extracted from paraffin-embedded diagnostic bone marrow biopsy specimens by heating paraffin slices at 100°C for 20 minutes in the solution containing 2% sodium dodecyl sulfate and 25 mM EDTA (ethylenediaminetetraacetic acid), followed by digestion at 50°C with proteinase K. Protein was removed by precipitation with 0.33 vol of 10 M ammonium acetate and centrifugation. DNA was recovered from the supernatant by alcohol precipitation. Pyrosequencing We developed 2 independent assays to detect the 1849G>T JAK2 mutation on the sense and antisense DNA strands. Exon 12 of JAK2 was amplified by polymerase chain reaction (PCR) from genomic DNA by primers JAK200F 5'-GCAGAGAGAATTTTCTGAACTAT and JAK200Rbio 5'biotin-CTCTGAGAAAGGCATTAGAAAG for the sense assay and JAK115Fbio 5'biotin-GCAGCAAGTATGATGAGCA and JAK115R 5'-CTCTGAGAAAGGCATTAGAAAG for the antisense assay. After PCR, the biotinylated strand was captured on streptavidin Sepharose beads (Amersham Biosciences, Uppsala, Sweden) and annealed with the sequencing primers JAK200S 5'-GGTTTTAAATTATGGAGTATGT for the sense strand and JAK115S 5'-TCTCGTCTCCACAGA for the antisense strand. Pyrosequencing was performed separately for the sense and antisense strands using PSQ HS 96 Gold SNP Reagents and the PSQ HS 96 pyrosequencing machine (Biotage, Uppsala, Sweden). The protocol for sample preparation and pyrosequencing is described in detail by Jones et al.14 Statistical analysis The correlation between the pyrosequencing assays detecting the 1849G>T mutation on the sense and antisense strands and the linearity of the assays were assessed by linear regression analysis. Differences in clinical parameters between the groups of patients with or without the mutation were analyzed by parametric or nonparametric t tests.    Results and discussion Top Abstract Introduction Study design Results and discussion References   JAK2 1849G>T mutation status was analyzed by 2 independent pyrosequencing assays in 374 samples of patients with hematologic neoplasms, 21 leukemic cell lines, and 40 healthy controls. Examples of pyrograms are shown in Figure 1A. We observed a nearly perfect correlation of the results from the pyrosequencing assays on the sense and antisense DNA strands (Figure 1B), confirming the accuracy and reproducibility (r2 = 0.99; P < .001) of the method. To examine the linearity of the assay, we performed titrations by mixing DNA from healthy controls with DNA from patients with 50% or 80% of mutant allele, respectively. DNA mixes containing different ratios of healthy control and patient DNA were amplified by PCR and analyzed by pyrosequencing. Figure 1C demonstrates a linear relationship between the content of patient DNA and the quantity of mutant allele detected by pyrosequencing (r2 = 0.99). The experiments suggested the lower detection limit of 5% to 10% mutant allele. Our analysis of various hematologic malignancies confirmed the high prevalence of JAK2 mutation in PV (25 [86%] of 29 patients), MF (18 [95%] of 19 patients), and ET (3 [30%] of 10 patients). We next analyzed the role of the JAK2 mutation in the progression of these disorders to AML. In 22 AML patients with preexisting PV, ET, or MF, 12 (55%) had the JAK2 mutation. This prevalence of the JAK2 mutation was lower compared with that in all ET/PV/MF patients studied in whom the JAK2 mutation was present (46 [79%] of 58 patients). This difference was significant by the Fisher exact test (2-sided; P = .047). When broken into individual MPD diagnoses, the prevalence of the JAK2 mutation in 9 AML patients with antecedent PV was lower (5 [56%] of 9 patients) than in the total group of PV patients studied (25 [86%] of 29; P = .07). This difference was even more striking in patients with myelofibrosis. None of 5 AML patients with preceding myelofibrosis had the JAK2 mutation, whereas the mutation was present in 18 (95%) of 19 of our patients with myelofibrosis (P < .001). Interestingly, a reverse pattern was seen in patients with ET. A higher prevalence of the JAK2 mutation was observed in AML patients than in those with antecedent ET (7 [88%] of 8), whereas we found the mutation in only 3 of 10 ET patients studied. Remarkably, the age at diagnosis of AML with antecedent PV/ET/MF was significantly lower (P = .04; t test) in patients lacking the JAK2 mutation (median, 58 years; range, 40-73 years) than in patients carrying the mutation (median, 68 years; range, 57-82 years), suggesting a more aggressive disease in MF and PV patients without the JAK2 mutation. In these patients, there also was an 8-year difference in the median age at PV, ET, or MF diagnosis in patients without the JAK2 mutation (age, 50 years; range, 24-71 years) than in those with the mutation (age, 58 years; range, 41-68 years), but this difference was not significant (P = .15). In 4 patients, we had access to samples at MPD and progression from the same patients. The mutation was present in PV and progression samples at approximately the same proportions as in mutant allele (32% and 71% at PV, compared with 49% and 74% at MF, and 0% and 85% at PV, compared with 0% and 85% in AML). These data suggest the deviation from the expected 50% and 100% results from contamination of the clonal cells by polyclonal cells not bearing the somatic JAK2 mutation (eg, T cells, stromal cells)16 and that the mutation occurs early in disease development. Overall, the data suggest the JAK2 1849G>T mutation is common in MPD but not critical for transformation to the acute phase of these diseases. Further studies in larger sets of patients and multivariate analysis for confounding factors are needed to confirm this observation. View larger version (16K): [in this window] [in a new window]   Figure 1.. Pyrosequencing assay for detection of 1849G>T JAK2 mutation. (A) Examples of pyrosequencing results. The sequence read is (G/T)TCTGTGG. The mutation site with the adjacent T nucleotide is shaded. Peak heights are proportional to the amount of nucleotide present in the sequenced DNA. (top panel) Results from healthy control showing equal heights of the 1849G and the following T peak. The last peak is of double height, reflecting 2 adjacent G nucleotides. (middle panel) Ph–CML, with the normal G allele constituting 40% and the mutant T allele 60% of the total amplified DNA. (bottom panel) HEL cell line showing 0% of normal G allele and 100% of mutant T allele. The height of the T peak is 200% (100% from the mutant allele and 100% from the adjacent T allele). (B) Reproducibility of quantitative analysis of the JAK2 mutation. Two independent PCR and pyrosequencing reactions were performed to quantify the presence of A on the antisense strand (x-axis) and T on the sense strand (y-axis). Correlation between the assays was nearly perfect (r2 = 0.99). (C) Titration experiments showed linearity of the pyrosequencing assay. Healthy control DNA was mixed with 10%, 25%, 50%, and 75% DNA from a patient with MF carrying 50% of the mutant allele (, broken line) or from a patient with PV whose DNA contained 80% of the mutant allele (, solid line). Linear regression showed slopes of 0.47 and 0.77 and correlation coefficients (r2) of 0.98 and 0.99, respectively. (D) JAK2 gene is amplified in HEL erythroleukemic cell line. Healthy control DNA mixed with 25%, 50%, and 75% HEL DNA showed 40%, 67%, and 85% of mutant allele (), indicating that the HEL cell line carries 4 mutant alleles and no normal allele. After correction for copy number, the dilution experiment showed a straight line (, solid line).   No mutations were found in 99 patients with Philadelphia chromosome (Ph)–positive CML (including 55 patients with imatinib-resistant disease), AML M0-M5 (20 patients), erythroleukemia (8 patients), or ALL (20 patients), but 2 of 11 patients with megakaryocytic leukemia (AML M7) were positive for the 1849G>T JAK2 mutation. In Ph– CML, we found the mutation in 3 (19%) of 16 patients. In CMML, 7 (13%) of 52 patients had the mutation. In MDS, the mutation was found in only 1 of 68 patients. None of these patients had an antecedent history of PV or MF. Individual characteristics of the non–PV/ET/MF patients carrying the 1849G>T JAK2 mutation are summarized in Table 1.17,18 In 4 patients, the proportion of mutant allele was lower than 20%, suggesting the presence of minor populations of cells carrying the mutation. We confirmed the presence of the mutant allele in all these patients by cloning PCR products in a plasmid vector and pyrosequencing 50 clones for each patient. In 9 of 13 patients, the sample studied was obtained within 6 months of diagnosis, indicating that the abnormality was acquired early rather than at disease progression. Mutation status for N-RAS and K-RAS was available in 79 patients studied here. JAK2 mutation was found in none of 9 patients positive for RAS mutations, compared with 7 of 70 patients free of RAS mutations. This difference was not statistically significant. View this table: [in this window] [in a new window]   Table 1.. Characteristics of patients with JAK2 mutations (other than PV/MF/ET)   Finally, we analyzed 21 leukemia cell lines. We detected the mutation in only the HEL erythroleukemic cell line, as reported,8 and showed amplification of the mutant allele (Figure 1D). No mutation was found in 12 other myeloid (BV173, HL60, K562, K5MBR, KG1, KG1a, ML1, MV4:11, NB4, OCI-AML3, TF1, U937), 4 T-cell (CEM, Jurkat, MOLT4, TALL), or 3 B-cell lines (BJAB, Raji, RS4:11). In summary, our results confirm previous reports on the prevalence of JAK2 mutations in PV, MF, ET, CMML, and MDS.6-10,13,14 Our data suggest that the JAK2 mutation is acquired early, indicating that other molecular events are required for progression. JAK2 mutation was found in a lower proportion of patients whose MF or PV progressed to AML, and the age of AML onset was 10 years lower in patients lacking the JAK2 mutation. This may indicate that patients with MF and PV but without the JAK2 mutation represent a subgroup with more aggressive disease or that AML developed from a different subpopulation of stem cells than did PV. JAK2 mutation is rare in other hematologic malignancies except CMML, Ph– CML, and megakaryocytic leukemia. Further studies of the clinical significance of the JAK2 mutation in these diseases will be of interest.    Footnotes   Submitted May 5, 2005; accepted July 9, 2005. Prepublished online as Blood First Edition Paper, July 21, 2005; DOI 10.1182/blood-2005-05-1800. Supported in part by the Leukemia SPORE grant P50CA100632 from the National Institutes of Health and by funds from the Physicians Referral Service at the University of Texas M.D. Anderson Cancer Center. J.J. designed the study and performed research and data analysis and wrote the manuscript. Y.O. substantially participated in the research, analyzed clinical data, and participated in writing and editing the manuscript. V.G. performed JAK2 mutation analysis in CML patients. C.B.R. critically evaluated and provided bone marrow biopsy specimens. J.T. Prchal contributed to the manuscript concept, referred some patients, critically evaluated data, and participated in composing and editing the manuscript. S.V. contributed to the manuscript concept, referred patients, and critically evaluated data. M.B., E.E., and H.K. referred patients and critically evaluated data and the manuscript. J.P.J.I. designed the study, provided blood and bone marrow samples, analyzed and critically evaluated data, and wrote the manuscript. An Inside Blood analysis of this article appears at the front of this issue. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734. Reprints: Jaroslav Jelinek, Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Unit 428, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: jjelinek{at}mdanderson.org.    References Top Abstract Introduction Study design Results and discussion References   Witthuhn BA, Quelle FW, Silvennoinen O, et al. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell. 1993; 74: 227-236.[CrossRef][Medline] [Order article via Infotrieve] Parganas E, Wang D, Stravopodis D, et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell. 1998;93: 385-395.[CrossRef][Medline] [Order article via Infotrieve] Peeters P, Raynaud SD, Cools J, et al. Fusion of TEL, the ETS-variant gene 6 (ETV6), to the receptor-associated kinase JAK2 as a result of t(9; 12) in a lymphoid and t(9;15;12) in a myeloid leukemia. Blood. 1997;90: 2535-2540.[Abstract/Free Full Text] Nunez CA, Zipf TF, Roberts WM, Medeiros LJ, Hayes K, Bueso-Ramos CE. Molecular monitoring of cerebrospinal fluid can predict clinical relapse in acute lymphoblastic leukemia with eosinophilia. Arch Pathol Lab Med. 2003;127: 601-605.[Medline] [Order article via Infotrieve] Reiter A, Walz C, Watmore A, et al. The t(8; 9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2. Cancer Res. 2005;65: 2662-2667.[Abstract/Free Full Text] 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] Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365: 1054-1061.[Medline] [Order article via Infotrieve] 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] 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.[Abstract/Free Full Text] Zhao R, Xing S, Li Z, et al. Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem. 2005;280: 22788-22792.[Abstract/Free Full Text] Marchioli R, Finazzi G, Landolfi R, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol. 2005;23: 2224-2232.[Abstract/Free Full Text] Mesa RA, Li CY, Ketterling RP, Schroeder GS, Knudson RA, Tefferi A. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood. 2005;105: 973-977.[Abstract/Free Full Text] Steensma DP, Dewald GW, Lasho TL, et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and the myelodysplastic syndrome. Blood. 2005;106: 1207-1209.[Abstract/Free Full Text] Jones AV, Kreil S, Zoi K, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood. Prepublished on May 26, 2005, as DOI 10.1182/blood-2005-03-1320. Ahmadian A, Gharizadeh B, Gustafsson AC, et al. Single-nucleotide polymorphism analysis by pyrosequencing. Anal Biochem. 2000;280: 103-110.[CrossRef][Medline] [Order article via Infotrieve] Prchal JT. Polycythemia vera and other primary polycythemias. Curr Opin Hematol. 2005;12: 112-116.[CrossRef][Medline] [Order article via Infotrieve] Onida F, Ball G, Kantarjian HM, et al. Characteristics and outcome of patients with Philadelphia chromosome negative, bcr/abl negative chronic myelogenous leukemia. Cancer. 2002;95: 1673-1684.[CrossRef][Medline] [Order article via Infotrieve] Onida F, Kantarjian HM, Smith TL, et al. Prognostic factors and scoring systems in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients. Blood. 2002;99: 840-849.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: V617F "JAKs" up myeloproliferative signal Ayalew Tefferi Blood 2005 106: 3335-3336. [Full Text] [PDF] Related Letter in Blood Online: Rare occurrence of the JAK2 V617F mutation in AML subtypes M5, M6, and M7 Stefan Fröhling, Daniel B. Lipka, Sabine Kayser, Claudia Scholl, Richard F. Schlenk, Hartmut Döhner, D. Gary Gilliland, Ross L. Levine, and Konstanze Döhner Blood 2006 107: 1242-1243. [Full Text] [PDF] This article has been cited by other articles: A Pich, L Riera, F Sismondi, L Godio, L D. Bonino, F Marmont, and P F. di Celle JAK2V617F activating mutation is associated with the myeloproliferative type of chronic myelomonocytic leukaemia J. Clin. Pathol., September 1, 2009; 62(9): 798 - 801. [Abstract] [Full Text] [PDF] H. Andrikovics, N. Meggyesi, A. Szilvasi, J. Tamaska, G. Halm, S. Lueff, S. Nahajevszky, M. Egyed, J. Varkonyi, G. Mikala, et al. HFE C282Y Mutation as a Genetic Modifier Influencing Disease Susceptibility for Chronic Myeloproliferative Disease Cancer Epidemiol. Biomarkers Prev., March 1, 2009; 18(3): 929 - 934. [Abstract] [Full Text] [PDF] S. Schnittger, U. Bacher, C. Haferlach, T. Geer, P. Muller, J. Mittermuller, P. Petrides, R. Schlag, R. Sandner, J. Selbach, et al. Detection of JAK2 exon 12 mutations in 15 patients with JAK2V617F negative polycythemia vera Haematologica, March 1, 2009; 94(3): 414 - 418. [Abstract] [Full Text] [PDF] E. Lippert, F. Girodon, E. Hammond, J. Jelinek, N. S. Reading, B. Fehse, K. Hanlon, M. Hermans, C. Richard, S. Swierczek, et al. Concordance of assays designed for the quantification of JAK2V617F: a multicenter study Haematologica, January 1, 2009; 94(1): 38 - 45. [Abstract] [Full Text] [PDF] A. Theocharides, J. R. Passweg, M. Medinger, R. Looser, S. Li, H. Hao-Shen, A. S. Buser, A. Gratwohl, A. Tichelli, and R. C. Skoda The allele burden of JAK2 mutations remains stable over several years in patients with myeloproliferative disorders Haematologica, December 1, 2008; 93(12): 1890 - 1893. [Abstract] [Full Text] [PDF] R. L. Levine and D. G. Gilliland Myeloproliferative disorders Blood, September 15, 2008; 112(6): 2190 - 2198. [Abstract] [Full Text] [PDF] C. S. Tam, R. M. Nussenzveig, U. Popat, C. E. Bueso-Ramos, D. A. Thomas, J. A. Cortes, R. E. Champlin, S. E. Ciurea, T. Manshouri, S. M. Pierce, et al. The natural history and treatment outcome of blast phase BCR-ABL- myeloproliferative neoplasms Blood, September 1, 2008; 112(5): 1628 - 1637. [Abstract] [Full Text] [PDF] J. P. Maciejewski and G. J. Mufti Whole genome scanning as a cytogenetic tool in hematologic malignancies Blood, August 15, 2008; 112(4): 965 - 974. [Abstract] [Full Text] [PDF] H. Kroeger, J. Jelinek, M. R. H. Estecio, R. He, K. Kondo, W. Chung, L. Zhang, L. Shen, H. M. Kantarjian, C. E. Bueso-Ramos, et al. Aberrant CpG island methylation in acute myeloid leukemia is accentuated at relapse Blood, August 15, 2008; 112(4): 1366 - 1373. [Abstract] [Full Text] [PDF] S. Xing, T. H. Wanting, W. Zhao, J. Ma, S. Wang, X. Xu, Q. Li, X. Fu, M. Xu, and Z. J. Zhao Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice Blood, May 15, 2008; 111(10): 5109 - 5117. [Abstract] [Full Text] [PDF] A. Pardanani, B. L. Fridley, T. L. Lasho, D. G. Gilliland, and A. Tefferi Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders Blood, March 1, 2008; 111(5): 2785 - 2789. [Abstract] [Full Text] [PDF] A. Hama, H. Yagasaki, Y. Takahashi, K. Matsumoto, H. Kiyoi, and S. Kojima Response: Mutations of JAK2, JAK3 and GATA1 in acute megakaryoblastic leukemia of Down syndrome Blood, February 15, 2008; 111(4): 2493 - 2494. [Full Text] [PDF] J. W. Tyner, D. K. Walters, S. G. Willis, M. Luttropp, J. Oost, M. Loriaux, H. Erickson, A. S. Corbin, T. O'Hare, M. C. Heinrich, et al. RNAi screening of the tyrosine kinome identifies therapeutic targets in acute myeloid leukemia Blood, February 15, 2008; 111(4): 2238 - 2245. [Abstract] [Full Text] [PDF] Y. Oki, J. Jelinek, L. Shen, H. M. Kantarjian, and J.-P. J. Issa Induction of hypomethylation and molecular response after decitabine therapy in patients with chronic myelomonocytic leukemia Blood, February 15, 2008; 111(4): 2382 - 2384. [Abstract] [Full Text] [PDF] C. James The JAK2V617F Mutation in Polycythemia Vera and Other Myeloproliferative Disorders: One Mutation for Three Diseases? Hematology, January 1, 2008; 2008(1): 69 - 75. [Abstract] [Full Text] [PDF] R. L. Levine and M. Heaney New Advances in the Pathogenesis and Therapy of Essential Thrombocythemia Hematology, January 1, 2008; 2008(1): 76 - 82. [Abstract] [Full Text] [PDF] A. Ferrajoli, S. Faderl, Q. Van, P. Koch, D. Harris, Z. Liu, I. Hazan-Halevy, Y. Wang, H. M. Kantarjian, W. Priebe, et al. WP1066 Disrupts Janus Kinase-2 and Induces Caspase-Dependent Apoptosis in Acute Myelogenous Leukemia Cells Cancer Res., December 1, 2007; 67(23): 11291 - 11299. [Abstract] [Full Text] [PDF] G. Barosi, G. Bergamaschi, M. Marchetti, A. M. Vannucchi, P. Guglielmelli, E. Antonioli, M. Massa, V. Rosti, R. Campanelli, L. Villani, et al. JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis Blood, December 1, 2007; 110(12): 4030 - 4036. [Abstract] [Full Text] [PDF] G. L. Chen and J. T. Prchal X-linked clonality testing: interpretation and limitations Blood, September 1, 2007; 110(5): 1411 - 1419. [Abstract] [Full Text] [PDF] J. T. Prchal The amount of JAK2 617V>F matters Blood, August 1, 2007; 110(3): 796 - 797. [Full Text] [PDF] A. M. Vannucchi, E. Antonioli, P. Guglielmelli, A. Rambaldi, G. Barosi, R. Marchioli, R. M. Marfisi, G. Finazzi, V. Guerini, F. Fabris, et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia Blood, August 1, 2007; 110(3): 840 - 846. [Abstract] [Full Text] [PDF] A. Theocharides, M. Boissinot, F. Girodon, R. Garand, S.-S. Teo, E. Lippert, P. Talmant, A. Tichelli, S. Hermouet, and R. C. Skoda Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood, July 1, 2007; 110(1): 375 - 379. [Abstract] [Full Text] [PDF] K. Hussein, O. Bock, A. Seegers, M. Flasshove, F. Henneke, G. Buesche, and H. H. Kreipe Myelofibrosis evolving during imatinib treatment of a chronic myeloproliferative disease with coexisting BCR-ABL translocation and JAK2V617F mutation Blood, May 1, 2007; 109(9): 4106 - 4107. [Full Text] [PDF] Q. Chen, P. Lu, A. V. Jones, N. C.P. Cross, R. T. Silver, and Y. L. Wang Amplification Refractory Mutation System, a Highly Sensitive and Simple Polymerase Chain Reaction Assay, for the Detection of JAK2 V617F Mutation in Chronic Myeloproliferative Disorders J. Mol. Diagn., April 1, 2007; 9(2): 272 - 276. [Abstract] [Full Text] [PDF] M. C. Yoder, L. E. Mead, D. Prater, T. R. Krier, K. N. Mroueh, F. Li, R. Krasich, C. J. Temm, J. T. Prchal, and D. A. Ingram Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals Blood, March 1, 2007; 109(5): 1801 - 1809. [Abstract] [Full Text] [PDF] Z. Li, M. Xu, S. Xing, W. T. Ho, T. Ishii, Q. Li, X. Fu, and Z. J. Zhao Erlotinib Effectively Inhibits JAK2V617F Activity and Polycythemia Vera Cell Growth J. Biol. Chem., February 9, 2007; 282(6): 3428 - 3432. [Abstract] [Full Text] [PDF] L. M. Scott, W. Tong, R. L. Levine, M. A. Scott, P. A. Beer, M. R. Stratton, P. A. Futreal, W. N. Erber, M. F. McMullin, C. N. Harrison, et al. JAK2 Exon 12 Mutations in Polycythemia Vera and Idiopathic Erythrocytosis N. Engl. J. Med., February 1, 2007; 356(5): 459 - 468. [Abstract] [Full Text] [PDF] X. Xu, Q. Zhang, J. Luo, S. Xing, Q. Li, S. B. Krantz, X. Fu, and Z. J. Zhao JAK2V617F: prevalence in a large Chinese hospital population Blood, January 1, 2007; 109(1): 339 - 342. [Abstract] [Full Text] [PDF] P. J. Campbell and A. R. Green The Myeloproliferative Disorders N. Engl. J. Med., December 7, 2006; 355(23): 2452 - 2466. [Full Text] [PDF] P. J. Campbell, E. J. Baxter, P. A. Beer, L. M. Scott, A. J. Bench, B. J. P. Huntly, W. N. Erber, R. Kusec, T. S. Larsen, S. Giraudier, et al. Mutation of JAK2 in the myeloproliferative disorders: timing, clonality studies, cytogenetic associations, and role in leukemic transformation Blood, November 15, 2006; 108(10): 3548 - 3555. [Abstract] [Full Text] [PDF] T. Mercher, G. Wernig, S. A. Moore, R. L. Levine, T.-L. Gu, S. Frohling, D. Cullen, R. D. Polakiewicz, O. A. Bernard, T. J. Boggon, et al. JAK2T875N is a novel activating mutation that results in myeloproliferative disease with features of megakaryoblastic leukemia in a murine bone marrow transplantation model Blood, October 15, 2006; 108(8): 2770 - 2779. [Abstract] [Full Text] [PDF] H. Szpurka, R. Tiu, G. Murugesan, S. Aboudola, E. D. Hsi, K. S. Theil, M. A. Sekeres, and J. P. Maciejewski Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation Blood, October 1, 2006; 108(7): 2173 - 2181. [Abstract] [Full Text] [PDF] D. P. Steensma JAK2 V617F in Myeloid Disorders: Molecular Diagnostic Techniques and Their Clinical Utility: A Paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology J. Mol. Diagn., September 1, 2006; 8(4): 397 - 411. [Abstract] [Full Text] [PDF] O. Bock, J. Neuse, K. Hussein, K. Brakensiek, G. Buesche, T. Buhr, B. Wiese, and H. Kreipe Aberrant Collagenase Expression in Chronic Idiopathic Myelofibrosis Is Related to the Stage of Disease but Not to the JAK2 Mutation Status Am. J. Pathol., August 1, 2006; 169(2): 471 - 481. [Abstract] [Full Text] [PDF] T. Horn, M. Kremer, T. Dechow, W. M. Pfeifer, B. Geist, M. Perker, J. Duyster, L. Quintanilla-Martinez, and F. Fend Detection of the Activating JAK2 V617F Mutation in Paraffin-Embedded Trephine Bone Marrow Biopsies of Patients with Chronic Myeloproliferative Diseases J. Mol. Diagn., July 1, 2006; 8(3): 299 - 304. [Abstract] [Full Text] [PDF] C. Bellanne-Chantelot, I. Chaumarel, M. Labopin, F. Bellanger, V. Barbu, C. De Toma, F. Delhommeau, N. Casadevall, W. Vainchenker, G. Thomas, et al. Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders Blood, July 1, 2006; 108(1): 346 - 352. [Abstract] [Full Text] [PDF] G. Wernig, T. Mercher, R. Okabe, R. L. Levine, B. H. Lee, and D. G. Gilliland Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model Blood, June 1, 2006; 107(11): 4274 - 4281. [Abstract] [Full Text] [PDF] A. I. Schafer Molecular basis of the diagnosis and treatment of polycythemia vera and essential thrombocythemia Blood, June 1, 2006; 107(11): 4214 - 4222. [Abstract] [Full Text] [PDF] U. Popat, A. Frost, E. Liu, Y. Guan, A. Durette, V. Reddy, and J. T. Prchal High levels of circulating CD34 cells, dacrocytes, clonal hematopoiesis, and JAK2 mutation differentiate myelofibrosis with myeloid metaplasia from secondary myelofibrosis associated with pulmonary hypertension Blood, May 1, 2006; 107(9): 3486 - 3488. [Abstract] [Full Text] [PDF] S. Frohling, D. B. Lipka, S. Kayser, C. Scholl, R. F. Schlenk, H. Dohner, D. G. Gilliland, R. L. Levine, and K. Dohner Rare occurrence of the JAK2 V617F mutation in AML subtypes M5, M6, and M7 Blood, February 1, 2006; 107(3): 1242 - 1243. [Full Text] [PDF] R. L. Levine and G. Wernig Role of JAK-STAT Signaling in the Pathogenesis of Myeloproliferative Disorders Hematology, January 1, 2006; 2006(1): 233 - 239. [Abstract] [Full Text] [PDF] This Article Abstract Full Text (PDF) All Versions of this Article: 2005-05-1800v1 106/10/3370    most recent 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 Jelinek, J. Articles by Issa, J.-P. J. Search for Related Content PubMed PubMed Citation Articles by Jelinek, J. Articles by Issa, J.-P. J. Related Collections Neoplasia Oncogenes and Tumor Suppressors Free Research Articles Brief Reports Clinical Trials and Observations Related Article in Blood Online Related Letter in Blood Online Social Bookmarking                   What's this?

	Copyright © 2005 by American Society of Hematology         Online ISSN: 1528-0020