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Blood, 15 September 2006, Vol. 108, No. 6, pp. 1865-1867.
Prepublished online as a Blood First Edition Paper on May 25, 2006; DOI 10.1182/blood-2006-01-013540.
 Previous Article | Table of Contents | Next Article 
HEMATOPOIESIS
Brief report
The JAK2-V617F mutation is frequently present at diagnosis in patients with essential thrombocythemia and polycythemia vera
Eric Lippert,
Marjorie Boissinot,
Robert Kralovics,
François Girodon,
Irène Dobo,
Vincent Praloran,
Nathalie Boiret-Dupré,
Radek C. Skoda, and
Sylvie Hermouet
From the Laboratoire d'Hématologie du CHU de Bordeaux, France; Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 601 (U601), Nantes, France; the Department of Research, Experimental Hematology, University Hospital Basel, Switzerland; Laboratoire d'Hématologie du CHU de Dijon, France; Laboratoire d'Hématologie du CHU d'Angers, France; Laboratoire d'Hématologie du CHU de Clermont-Ferrand, France; and Laboratoire d'Hématologie du CHU de Nantes, France.
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Abstract
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We determined the allelic frequency of the JAK2-V617F mutation in DNA and assessed the expression levels of the mutant and wild-type JAK2 mRNA in granulocytes from 60 patients with essential thrombocythemia (ET) and 62 patients with polycythemia vera (PV) at the time of diagnosis. Using allele-specific quantitative polymerase chain reaction (qPCR), we detected JAK2-V617F in 75% of ET and 97% of PV at diagnosis. The total JAK2 mRNA levels were elevated in ET, PV, and secondary and idiopathic erythrocytosis, suggesting that hyperactive hematopoiesis alters JAK2 expression. The expression levels of JAK2-V617F mRNA were variable but strongly correlated with the allelic ratio of JAK2-V617F determined in DNA. Thus, differences in JAK2-V617F expression, markedly lower in ET than in PV, reflected different percentages of granulocytes carrying the mutation. Moreover, allelic ratios higher than 50% JAK2-V617F, indicating the presence of granulocytes homozygous for JAK2-V617F, were found in 70% of PV at diagnosis but never in ET.
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Introduction
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Since the discovery of the JAK2-V617F mutation in BCR-ABL–negative myeloproliferative disorders (MPDs),1-4 several cohorts of patients were studied. Most reports agreed on the presence of JAK2-V617F in a large majority of polycythemia vera (PV), but the rate of positivity in essential thrombocythemia (ET) varied.1-8 Among the reasons for such differences are ET heterogeneity (patients were often treated), the criteria used for diagnosis, the type of cellular material studied, and the sensitivity of the techniques, allele-specific polymerase chain reaction (AS-PCR) revealing more mutations than sequencing or restriction fragment analysis. This prompted us to develop a sensitive, quantitative AS-PCR (AS-qPCR), which we used to examine patients addressed for diagnosis of polycythemia or thrombocytosis.
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Study design
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With informed consent and before treatment, blood and bone marrow (BM) samples from 62 PV and 60 ET, as well as 76 controls (24 secondary erythrocytosis [SE], 28 idiopathic erythrocytosis [IE], 24 reactive thrombocytosis), were collected in 5 centers. Blood was also obtained from 40 healthy donors (HDs) and 18 patients hospitalized for minor surgery. The study was approved by local Comité Consultatif de Protection des Personnes dans le Recherche Biomedicale de Bourgogne ethics committees.
The collagen endogenous colony assays and EPO dosage were described previously.9-12 Blood granulocytes were isolated from the lower interface of a Ficoll density gradient, then submitted to erythrocyte lysis. RNA or genomic DNA was extracted with Trizol (Invitrogen, Frederick, MD) or QiaAmp DNA mini-kit (Qiagen, Valencia, CA); the latter was also used for cells stained with May-Grünwald-Giemsa. The quantitative reverse-transcriptase (RT)–PCR assay of PRV-1 expression was performed as described.13,14
JAK2 AS-qPCRs and RT-qPCRs were performed with specific forward primers (wild-type JAK2 [JAK2-WT]: 5'-GCGCGGTTTTAAATTATGGAGTATGTG-3'; JAK2-V617F: 5'-GCGCGGTTTTAAATTATGGAGTATGTT-3'), common reverse primers (cDNA: 5'-CCGCTTTTTCAGATATGTATCTAGTGATCC-3'; DNA: 5'-GCGGTGATCCTGAAACTGAATTTTC-3'), and 6-FAM probes (cDNA: 5'-TGGAGACGAGAATATTCTGGTTCAGGAGTTTG-3'; DNA: 5'-TGGAGACGAGAGTAAGTAAAACTACAGGCT-3'). Copy numbers were determined by comparison with serial dilutions of plasmids obtained by cloning of JAK2 and ABL cDNA or DNA amplicons from U937 (WT) and HEL (V617F) cells into TOPO-TA vectors (Invitrogen).
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Results and discussion
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Patient characteristics and frequency of JAK2-V617F in ET and PV at diagnosis
Patients with erythrocytosis or thrombocytosis were diagnosed with PV, SE, ET, or RT according to Polycythemia Vera Study Group (PVSG) or World Health Organization (WHO) criteria.15-17 Patients with absolute erythrocytosis, no PV criteria, and no cause of SE were diagnosed with IE. At diagnosis, ET was characterized by endogenous megakaryocytic colonies (EMCs) (47/56 patients) and PV by low serum EPO (54/58 patients), increased PRV-1 expression (48/62), endogenous erythroid colonies (EECs) (50/59), and EMCs (30/49) (Figure 1). A minority of ET presented with increased PRV-1 (17/60), EECs (13/59), or low EPO (7/38); all had normal hematocrit or red cell mass, eliminating misdiagnosed PV.
In granulocyte cDNA, JAK2-V617F was never found in IE, SE, and RT, or in healthy donors and presurgery patients, but was present in 43 of 60 ET and 59 of 62 PV (Figure 1). In addition, the mutation was found in DNA from May-Grünwald-Giemsa–stained progenitors (1 BM smear and 2 EMCs) for 3 patients considered negative in granulocytes, raising the percentages of JAK2-V617F positivity to 75% (45/60) in ET and 97% (60/62) in PV. The high frequency of JAK2-V617F positivity in our ET series may be explained by the purity of the granulocyte preparations, the fact that diagnosis was established on the presence of EMCs (not a WHO criterion), in addition to BM histology, but mostly by the sensitivity (0.5%) of the qPCR. Indeed, using a different AS-qPCR, Levine et al detected a similar frequency of JAK2-V617F positivity in ET. Of note, the frequency of JAK2-V617F positivity in PV and ET is as high at diagnosis (this series) as after years of disease progression.1-8,18 Hence, detection of JAK2-V617F is an essential diagnostic test for both ET and PV. For the diagnosis of ET, the EMC assay is more sensitive than the detection of JAK2-V617F; it also allows molecular studies of EMCs, more likely to bear the mutation than unselected blood or BM cells.
Expression levels of JAK2-WT and JAK2-V617F mRNA in granulocytes
Relative expression of JAK2-WT and JAK2-V617F was quantitated against plasmidic standard dilutions and normalized for ABL expression. Granulocytes of IE and SE patients expressed significantly higher levels of JAK2-WT (medians: 348 and 452 JAK2-WT/100 ABL, P = .001 and P = .005, respectively) than healthy donors and presurgery patients (197 and 174 copies/100 ABL, respectively). When both JAK2-WT and JAK2-V617F were considered, PV and ET granulocytes also expressed significantly more total JAK2 than healthy donors and presurgery patients (median total JAK2/100 ABL: 680 in PV, P < .001; 303 in ET, P = .008), suggesting that chronic stimulation of hematopoiesis may up-regulate JAK2 expression.
The percentage of total JAK2 represented by JAK2-V617F (%V617F) in ET and in PV was then analyzed (Figure 1; Table 1). This percentage can be assimilated to the allelic ratio since %V617F was similar when assessed in cDNA and in genomic DNA from granulocytes of 40 patients (r = 0.90, P < .01; [%V617F in cDNA] = 1.03 x [%V617F in genomic DNA]). The percentages of mutant were not close to 50 or 100 as would be the case if all cells were exclusively heterozygous or homozygous for the mutant allele. Rather, they were distributed continuously, as if fractions of granulocytes had different allelic status. Thus, a percentage of mutants more than 50 is necessary and sufficient to affirm homozygosity. In positive PV, JAK2-V617F represented on average 62% of total JAK2 (median: 61%; range: 8%-98%). In all but one positive PV, JAK2-V617F represented more than 25% of total JAK2. Seventy percent of PV expressed more than 50% JAK2-V617F, implying that at least part of the granulocytes was homozygous for the V617F allele. In contrast, JAK2-V617F represented an average of 20% of total JAK2 in ET (P < .001 compared with PV), and all but one positive ET expressed less than 40% JAK2-V617F (median: 19%; range: 3%-50%). Thus, the 50% JAK2-V617F threshold revealed more "homozygous" PV at diagnosis than previously reported using sequencing and nonquantitative PCR.1-5 In ET, either the mechanisms leading to JAK2-V617F homozygosity do not exist, or homozygous clones are repressed.
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Figure 1.. Characteristics of ET and PV patients at diagnosis. Expression of JAK2-V617F and results of the PRV-1 assay, endogenous erythroid colony (EEC) and endogenous megakaryocytic colony (EMC) assays, and dosage of serum EPO are shown according to the percentage of total JAK2 represented by JAK2-V617F in blood granulocyte cDNAs. Filled rectangles show increased expression of PRV-1 (defined by a PRV-1 CT/ABL CT ratio < 0.850), positive EEC and EMC assays, and low (< 3.3 IU/L) serum EPO; open rectangles, normal PRV-1 expression, negative EEC and EMC assays, and normal or high serum EPO. Empty spaces mean that the assay was not performed.
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Effects of JAK2-V617F levels on hematopoietic lineages and disease phenotype
Percentages of JAK2-V617F correlated with granulocyte expression of PRV-1 (n = 92, r = 0.543, P < .001), confirming PRV-1 expression as a target of JAK2 signaling.19 In patients at diagnosis, JAK2-V617F levels correlated only with leukocyte counts (PV: n = 56, r = 0.496, P = .001; ET: n = 42, r = 0.314, P = .043), not with hemoglobin level, hematocrit level, platelet counts, numbers of EECs, or numbers of EMCs. Consistently, the level of mutant expression was not sufficient per se to determine PV or ET phenotype: comparison of PV and ET with similar levels of mutant (25%-40%) showed similar leukocyte counts, but PV patients had significantly higher EPO, EEC formation, red cell mass (152% vs 78%, P = .001), hematocrit, and hemoglobin level and lower platelet counts (Table 1). However, as recently described for ET,8 in our series of PV and ET at diagnosis, JAK2-V617F was associated with stimulation of erythropoiesis and repression of thrombopoiesis: PV with 75% or more mutant and positive ET differed from other PV and negative ET by higher hematocrit and hemoglobin levels, but lower platelet counts (Table 1).
In summary, sensitive qPCRs detected JAK2-V617F in 97% of PV and 75% of ET at diagnosis, with higher levels of expression in PV than in ET; cells homozygous for the mutation were present in 70% of PV. This demonstrates the interest of precise and sensitive assessment of JAK2-V617F for the diagnosis of MPD.
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Acknowledgements
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We wish to thank Prof James Casey (Cornell University, Ithaca, NY) and Dr François Davodeau (INSERM, U601, Nantes, France) for helpful discussions; Dr Céline Schaeffer for collecting patient data; and Mrs Danielle Pineau and Marina Migeon for excellent technical help. We are indebted to colleagues from the Departments of Clinical Hematology of the Centres Hospitaliers of Angers, Bayonne, Bordeaux, Châlon-sur-Saône, Clermont-Ferrand, Dax, Dijon, Laval, Libourne, Lorient, Nantes, La Roche-sur-Yon, and Saumur for providing samples.
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Footnotes
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Submitted January 24, 2006;
accepted May 8, 2006.
Prepublished online as Blood First Edition Paper, May 25, 2006; DOI 10.1182/blood-2006-01-013540.
Supported by grants from the Programme Hospitalier de Recherche Clinique of the Région Bourgogne and the Grand Ouest and Aquitaine committees of the Ligue Nationale contre le Cancer.
S.H. and R.C.S. conceived the study; E.L. and S.H. performed qPCRs and qRT-PCRs, analyzed the data, did statistical analyses, and wrote the paper; M.B. and R.K. performed qPCRs, qRT-PCRs, and sequencing; F.G., I.D., V.P., and N.B.-D. provided samples and acquired clinical and biologic data; and F.G. is responsible for the patient database.
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: Sylvie Hermouet, Laboratoire d'Hématologie, Institut de Biologie, 9 quai Moncousu, 44093 Nantes cedex, France; e-mail: sylvie.hermouet{at}chu-nantes.fr.
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Abstract
Introduction