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Use of the 46/1 haplotype to model JAK2V617F clonal architecture in PV patients: clonal evolution and impact of IFNα treatment

Leukemia volume 28, pages 460–463 (2014)Cite this article

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V617F mutation of the protein kinase JAK2 is the most prevalent genetic abnormality in the three myeloproliferative neoplasms (MPNs), namely polycythemia vera (PV, 95%), essential thrombocythemia (ET, 60%) and myelofibrosis (MF, 60%).1, 2, 3, 4 This mutation, which usually affects only one of the JAK2 gene alleles in ET, frequently becomes homozygous in PV and MF. This homozygosity is related to chromosome 9p uniparental disomy (UPD 9p) due to mitotic homologous recombination. It was recently shown that the 46/1 haplotype, defined by four single-nucleotide polymorphisms (SNPs: rs3780367, rs10974944, rs12343867 and rs1159782), was strongly associated with the cis acquisition of JAK2V617F mutation with complete linkage disequilibrium.5, 6, 7 As UPD 9p involves most of the chromosome 9, JAK2V617F and the SNPs that tag 46/1 are converted into homozygosity simultaneously, and the 46/1 SNP allele burden reflects the percentage of JAK2V617F/V617F cells in 46/1 heterozygous PV patients. The JAK2V617F allele burden depends on the fraction of cells with a wild type, heterozygous and homozygous genotype. These fractions are usually determined by single-cell analyses. Here, we report that the combined measurement of 46/1 SNPs and JAK2V617F allele burdens in hematopoietic progenitors and differentiated myeloid compartments allows dissecting the clonal architecture in each cell compartment. This approach can be used to explore the impact of treatments, as demonstrated in patients exposed to alpha-interferon (IFNα).

We first explored three patients with hemochromatosis, wild-type JAK2 and rs12343867 heterozygosity. Genotyping of 500 single-cell colonies established from sorted CD34+CD38− and CD34+CD38+ progenitors did not identify any rs12343867 homozygous colony (Supplementary Figure S1), indicating that recombination of the 46/1 haplotype was not a common event.

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Acknowledgements

We are grateful to Françoise Wendling and Caroline Marty for improving the manuscript. We thank Yann Lecluse and Philippe Rameau from the Imaging Platform for their help in cytometry analysis and cell sorting, and Yannis Dufourd and Noemie Pata-Merci from the Genomic Platform for NGS analysis. This work was supported by grants from the Agence Nationale de la Recherche (Epigenome 2010, Thrombocytosis 2011), the Foundation ARC (Association pour la Recherche contre le Cancer, IP), the Ligue Nationale contre le Cancer (WV, ES) and the “Investissements d’avenir” programme (Labex GR-Ex; IP, WV). HS, FF and BM-M were supported by fellowships from la Ligue Nationale Contre le Cancer, the Foundation ARC, and the Fondation pour la Recherche Médicale, respectively. WV is a recipient of a research fellowship from Gustave Roussy and INSERM (contrat d’interface). IP is supported by grants from Foundation ARC (projet libre 2012).

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  1. W Vainchenker and I Plo: These authors contributed equally to this work.

Authors and Affiliations

  1. INSERM, UMR 1009, Laboratory of Excellence GR-Ex, Villejuif, France

    S Hasan, N Droin, J P Le Couedic, F Favale, B Monte-Mor, C Lacout, E Solary, J L Villeval, N Casadevall, W Vainchenker & I Plo

  2. Université Paris-Sud, UMR 1009, Institut Gustave Roussy, Villejuif, France

    S Hasan, N Droin, J P Le Couedic, F Favale, B Monte-Mor, C Lacout, E Solary, J L Villeval, W Vainchenker & I Plo

  3. Gustave Roussy, Institut Gustave Roussy, Villejuif, France

    S Hasan, N Droin, J P Le Couedic, F Favale, B Monte-Mor, C Lacout, E Solary, J L Villeval, W Vainchenker & I Plo

  4. AP-HP, Service de Biologie Cellulaire, Hôpital Saint-Louis, Paris, France

    B Cassinat, C Dosquet & C Chomienne

  5. AP-HP, Hôpital Cochin, Service d’Hématologie biologique, Paris, France

    M Fontenay

  6. Université Paris-Diderot, Sorbonne Paris Cité, Paris, France,

    C Chomienne

  7. AP-HP, Laboratoire d’hématologie, Hôpital Saint Antoine, Paris, France

    N Casadevall

  8. AP-HP, Centre d'Investigations Cliniques, Hôpital Saint-Louis, Paris, France

    J J Kiladjian

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  1. S Hasan
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Hasan, S., Cassinat, B., Droin, N. et al. Use of the 46/1 haplotype to model JAK2V617F clonal architecture in PV patients: clonal evolution and impact of IFNα treatment. Leukemia 28, 460–463 (2014). https://doi.org/10.1038/leu.2013.303

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