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Pathologic activation of thrombopoietin receptor and JAK2-STAT5 pathway by frameshift mutants of mouse calreticulin

Leukemia volume 30, pages 1775–1778 (2016)Cite this article

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Frameshifting (−1/+2) mutations in the exon 9 of the calreticulin gene (CALR) lead to the development of BCR-ABL-negative myeloproliferative neoplasms (MPNs) in humans under the forms of essential thrombocythemia (ET) and myelofibrosis.1, 2 We have shown that mutant human CALR proteins require interaction with the thrombopoietin receptor (TpoR) to exert an oncogenic activation of the JAK/STAT pathway.3, 4 Here, we report that homologous mutations in the murine Calr gene result in a highly similar, but not identical mutant CALR protein as found in human patients that also requires TpoR interaction to be able to activate the JAK/STAT pathway.

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Acknowledgements

We thank Dr Patrick Jacquemin for the support with CRISPR/Cas9 approach and Dr Nicolas Dauguet for expert cell sorting. IP is supported by Institut National du Cancer (PLBIO2015); Agence Nationale de la Recherche; (ANR-13-JVSV1-GERMPN-01, I.P.) and Institut National de la Santé et de la Recherche Médicale, Genetics of Hematological Disorders (Inserm). IP, WV and CM are supported by a grant form la Ligue Nationale contre le Cancer (HR 2013, 2016). Support to SNC was from the Ludwig Institute for Cancer Research, FRS-FNRS, Salus Sanguinis Foundation, the Action de Recherche Concertée project ARC10/15–027 of the Université catholique de Louvain, the Fondation contre le Cancer, the PAI Programs BCHM61B5 and Belgian Medical Genetics Initiative. Support from Télévie (IC and TB), FSR (TB) and FRS-FNRS (CP) is acknowledged. HN and RK acknowledge the support received by Austrian Science Fund (FWF: project numbers- F2812-B20 and F4702-B20).

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Authors and Affiliations

  1. Ludwig Institute for Cancer Research Brussels, Brussels, Belgium,

    T Balligand, C Pecquet, I Chachoua & S N Constantinescu

  2. SIGN Pole, de Duve Institute, Université catholique de Louvain, Brussels, Belgium

    T Balligand, C Pecquet, I Chachoua & S N Constantinescu

  3. LPAD Pole, de Duve Institute, Université catholique de Louvain, Brussels, Belgium

    Y Achouri

  4. Genetics of Hematological Disorders, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

    H Nivarthi & R Kralovics

  5. INSERM, UMR1170, Villejuif, France

    C Marty, W Vainchenker & I Plo

  6. Paris-Saclay, UMR1170, Villejuif, France

    C Marty, W Vainchenker & I Plo

  7. Gustave Roussy, UMR1170, Villejuif, France

    C Marty, W Vainchenker & I Plo

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  1. T Balligand
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  2. Y Achouri
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  3. C Pecquet
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  6. C Marty
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  9. R Kralovics
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Correspondence to S N Constantinescu.

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Balligand, T., Achouri, Y., Pecquet, C. et al. Pathologic activation of thrombopoietin receptor and JAK2-STAT5 pathway by frameshift mutants of mouse calreticulin. Leukemia 30, 1775–1778 (2016). https://doi.org/10.1038/leu.2016.47

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