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JAK2 mutation and disease phenotype: a double L611V/V617F in cis mutation of JAK2 is associated with isolated erythrocytosis and increased activation of AKT and ERK1/2 rather than STAT5

Leukemia volume 24, pages 1069–1073 (2010)Cite this article

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Polycythemia vera (PV), a myeloproliferative neoplasm (MPN), is characterized by the presence of a mutated, activated form of the tyrosine kinase JAK2.1 In 95% of cases, PV patients present the V617F mutation in exon 14 (JAK2–V617F) and half of V617F-negative PV patients carry mutations or deletions in exon 12.2 Both types of mutations result in activation of JAK2 and STAT5. Recently the 46/1 (or ‘GGCC’) haplotype of chromosome 9p was found associated with a pre-disposition to JAK2 mutations in the same allele. As this haplotype is relatively frequent, unrecognized mutations of JAK2 may not be rare. Indeed healthy donors were reported positive for JAK2-V617F using nested PCR assays, and the repeated occurrence of the V617F mutation of JAK2 has been demonstrated in essential thrombocythemia (ET) and in PV.3, 4, 5 In addition, in 2 PV patients, JAK2-V617F and mutations in exon 12 of JAK2 co-existed in separate sub-clones originating from a single progenitor in one case, or from unrelated hematopoietic stem cells in the other case.6, 7 V617F-positive PV patients with additional mutation(s) in exon 14 of JAK2 (V615L, C616Y, C618R and D620E) are also evidence of multiple JAK2 mutations.8 As different JAK2 mutants may have different JAK2 activity, the JAK2 mutational status may influence subclone outcome and affect disease phenotype.

To address this question, we studied 3 PV patients found to be carriers of a new mutation in exon 14 of JAK2, leucine 611 changed for a valine (L611V) present in cis with V617F, that resulted in the double JAK2-L611V/V617F mutant. DNA and RNA extracted from purified granulocytes, platelets, CD3+ T-lymphocytes and colonies were analyzed using allele-specific quantitative PCR assays (AS-qPCRs), pyrosequencing and conventional sequencing.9, 10, 11 The primers and probes used are listed in Supplementary Table 1. With informed consent, DNA samples from 10 healthy donors, 199 control patients with idiopathic erythrocytosis (n=22), secondary erythrocytosis (n=148) or splanchnic vein thrombosis (n=29), and 465 patients diagnosed following the 2002 WHO criteria with PV (n=168), ET (n=271) or primary myelofibrosis (n=26) were analyzed, as were DNA from 31 archival samples from MPN transformed into acute myeloid leukemia.

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References

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Acknowledgements

We are indebted to colleagues of the Clinical Hematology Departments of the University Hospitals of Nantes and Dijon for providing patient samples; to Dr Radek Skoda (Basel, Switzerland) for murine BaF-3/Epo-R cells and JAK2-V617F cDNA; to Dr Serge Carillo for JAK2 exon 12 mutation analysis; to Dr Isabelle Corre for expert advice; and to Mrs Danielle Pineau for excellent technical help. The study was supported by grants from the Ligue Nationale contre le Cancer (Comité de Loire-Atlantique, Comité du Morbihan, Comité d’Ille-et-Vilaine) and from the Association pour la Recherche contre le Cancer (ARC). CC and MB benefited from scholarships from the French Ministry of Research.

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Authors and Affiliations

  1. INSERM UMR 892, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Institut de Recherche Thérapeutique-Universit,

    C Cleyrat, M Boissinot & S Hermouet

  2. é de Nantes (IRT-UN), Nantes, France

    C Cleyrat, M Boissinot & S Hermouet

  3. Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    J Jelinek & J-P Issa

  4. Laboratoire d’Hématologie, Centre Hospitalier Universitaire (CHU), Dijon, France

    F Girodon

  5. Service de Médecine Interne, CHU, Nantes, France

    T Ponge

  6. Department of Leukemia, The University of Texas M D Anderson Cancer Center, Houston, USA

    J-L Harousseau

  7. Laboratoire d’Hématologie, Institut de Biologie, CHU, Nantes, France

    S Hermouet

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  1. C Cleyrat
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Correspondence to S Hermouet.

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Cleyrat, C., Jelinek, J., Girodon, F. et al. JAK2 mutation and disease phenotype: a double L611V/V617F in cis mutation of JAK2 is associated with isolated erythrocytosis and increased activation of AKT and ERK1/2 rather than STAT5. Leukemia 24, 1069–1073 (2010). https://doi.org/10.1038/leu.2010.23

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