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Chronic myeloproliferative neoplasms

Mutant NRAS Q61K is responsible for MAPK pathway activation in the MARIMO cell line and renders these cells independent of the CALR–MPL–JAK2–STAT5 pathway

Leukemia volume 32, pages 2087–2090 (2018)Cite this article

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Calreticulin (CALR) is a chaperone localized in the endoplasmic reticulum (ER), mainly regulating protein folding and quality control processes. In 2013, somatic CALR mutations were discovered in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF), which did not harbor Janus kinase 2 (JAK2) or thrombopoietin receptor (MPL) mutations [1, 2]. Lately, the mechanisms of the oncogenic capacity of CALR frameshift mutants in the pathogenesis of myeloproliferative neoplasms (MPN) have been studied. Recent findings have highlighted the necessity of MPL expression for mutant CALR-induced cellular transformation [3,4,5]. The binding of CALR mutants via its glycan-binding site to the extracellular domain of MPL induces the constitutive activation of associated JAK2 and downstream signaling molecules, including STAT3/5, AKT, and ERK1/2, all of which can be inhibited by the JAK1/2 inhibitor ruxolitinib [3, 4, 6].

The MARIMO cell line is unique in that it carries a pathogenic CALR mutation, originally derived from bone marrow cells of a patient with secondary AML-M2 that had developed from a preexisting ET during busulfan treatment [7]. MARIMO cells harbor a heterozygous 61-bp deletion in CALR exon 9 (c.1099_1159del; L367Mfs*43), resulting in the +1 bp frameshift mutation similar to the two most prominent CALR mutations del52 and ins5.

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References

  1. Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:2379–90.

    Article  PubMed  CAS  Google Scholar 

  2. Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369:2391–405.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Chachoua I, Pecquet C, El-Khoury M, Nivarthi H, Albu R-I, Marty C, et al. Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants. Blood. 2016;127:1325–35.

    Article  PubMed  CAS  Google Scholar 

  4. Araki M, Yang Y, Masubuchi N, Hironaka Y, Takei H, Morishita S, et al. Activation of the thrombopoietin receptor by mutant calreticulin in CALR-mutant myeloproliferative neoplasms. Blood. 2016;127:1307–16.

    Article  PubMed  CAS  Google Scholar 

  5. Han L, Schubert C, Köhler J, Schemionek M, Isfort S, Brümmendorf TH, et al. Calreticulin-mutant proteins induce megakaryocytic signaling to transform hematopoietic cells and undergo accelerated degradation and Golgi-mediated secretion. J Hematol Oncol. 2016;9:45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Elf S, Abdelfattah NS, Chen E, Perales-Patón J, Rosen EA, Ko A, et al. Mutant calreticulin requires both its mutant C-terminus and the thrombopoietin receptor for oncogenic transformation. Cancer Discov. 2016;6:368–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Yoshida H, Kondo M, Ichihashi T, Hashimoto N, Inazawa J, Ohno R, et al. A novel myeloid cell line, Marimo, derived from therapy-related acute myeloid leukemia during treatment of essential thrombocythemia: consistent chromosomal abnormalities and temporary C-MYC gene amplification. Cancer Genet Cytogenet. 1998;100:21–4.

    Article  PubMed  CAS  Google Scholar 

  8. Kollmann K, Nangalia J, Warsch W, Quentmeier H, Bench A, Boyd E, et al. MARIMO cells harbor a CALR mutation but are not dependent on JAK2/STAT5 signaling. Leukemia. 2015;29:494–7.

    Article  PubMed  CAS  Google Scholar 

  9. Kollmann K, Warsch W, Gonzalez-Arias C, Nice FL, Avezov E, Milburn J, et al. A novel signalling screen demonstrates that CALR mutations activate essential MAPK signalling and facilitate megakaryocyte differentiation. Leukemia. 2017;31:934–44.

    Article  PubMed  CAS  Google Scholar 

  10. Kirschner M, Maurer A, Wlodarski MW, Ventura Ferreira MS, Bouillon A-S, Halfmeyer I, et al. Recurrent somatic mutations are rare in patients with cryptic dyskeratosis congenita. Leukemia. 2018. https://doi.org/10.1038/s41375-018-0125-x.

  11. Li A, Ma Y, Jin M, Mason S, Mort RL, Blyth K, et al. Activated mutant NRas(Q61K) drives aberrant melanocyte signaling, survival, and invasiveness via a Rac1-dependent mechanism. J Invest Dermatol. 2012;132:2610–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

We acknowledge Dr. Anthony Green for providing the MARIMO cells. We thank Dr. Hitoshi Kiyoi and Dr. Yuichi Ishikawa for providing the Materials Transfer Agreement (MTA) and the permission to use the cells. This study was in part supported by grants to SK from the German Research Foundation (DFG KO2155/6-1) and the Deutsche José Carreras Leukämie-Stiftung (DJCLS 16R/2017).

Author contributions

LH, NC, and SK designed the research; LH, JC, and AM performed the research; LH wrote the manuscript; and LH, AM, THB, NC, and SK analyzed the data and revised the manuscript. All authors approved the final version of the manuscript.

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  1. These authors contributed equally: Nicolas Chatain, Steffen Koschmieder

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  1. Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen, Germany

    Lijuan Han, Julia Czech, Angela Maurer, Tim H. Brümmendorf, Nicolas Chatain & Steffen Koschmieder

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Correspondence to Steffen Koschmieder.

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Conflict of interest

THB has participated in advisory boards and satellite symposia for Ariad, Bristol-Myers Squibb, Merck, Novartis, and Pfizer (no personal honoraria); he has received research funding from Novartis and Pfizer and holds a patent on the combination of imatinib with hypusination inhibitors. SK is a member of the Advisory Boards of Pfizer, Incyte/Ariad, Novartis, AOP, BMS, and CTI; Honoraria: Novartis, BMS, Pfizer, Incyte/Ariad, and Shire; Scientific Research Support: Novartis Foundation, BMS, and Novartis; Others: Alexion. The remaining authors declare that they have no conflict of interest.

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Han, L., Czech, J., Maurer, A. et al. Mutant NRAS Q61K is responsible for MAPK pathway activation in the MARIMO cell line and renders these cells independent of the CALR–MPL–JAK2–STAT5 pathway. Leukemia 32, 2087–2090 (2018). https://doi.org/10.1038/s41375-018-0234-6

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