期刊
BLOOD
卷 127, 期 10, 页码 1325-1335出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-11-681932
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资金
- Institut National du Cancer [PLBIO2015]
- Agence Nationale de la Recherche
- Programme Jeunes Chercheuses et Jeunes Chercheurs [ANR-13-JVSV1-GERMPN-01]
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- la Ligue Nationale contre le Cancer
- Ludwig Institute for Cancer Research
- FRS-FNRS
- Salus Sanguinis Foundation
- Action de Recherche Concertee project of the Universite catholique de Louvain [ARC10/15-027]
- Fondation contre le Cancer
- PAI Programs [BCHM61B5]
- Belgian Medical Genetics Initiative
- FRIA fellowship
- Televie fellowship
- FNRS-Aspirant fellowship
- Cliniques universitaires St-Luc, Brussels
- Belspo postdoctoral fellowship
- Austrian Science Fund (FWF) [F2812-B20, F4702-B20]
Mutations in the calreticulin gene (CALR) represented by deletions and insertions in exon 9 inducing a -1/+2 frameshift are associated with a significant fraction of myeloproliferative neoplasms (MPNs). The mechanisms by which CALR mutants induce MPN are unknown. Here, we show by transcriptional, proliferation, biochemical, and primary cell assays that the pathogenic CALR mutants specifically activate the thrombopoietin receptor (TpoR/MPL). No activation is detected with a battery of type I and II cytokine receptors, except granulocyte colony-stimulating factor receptor, which supported only transient and weak activation. CALR mutants induce ligand-independent activation of JAK2/STAT/phosphatydylinositol-3'-kinase (PI3-K) and mitogen-activated protein (MAP) kinase pathways via TpoR, and autonomous growth in Ba/F3 cells. In these transformed cells, no synergy is observed between JAK2 and PI3-K inhibitors in inhibiting cytokine-independent proliferation, thus showing a major difference from JAK2V617F cells where such synergy is strong. TpoR activation was dependent on its extracellular domain and its N-glycosylation, especially at N117. The glycan binding site and the novel C-terminal tail of the mutant CALR proteins were required for TpoR activation. A soluble form of TpoR was able to prevent activation of full-length TpoR provided that it was N-glycosylated. By confocal microscopy and subcellular fractionation, CALR mutants exhibit different intracellular localization from that of wild-type CALR. Finally, knocking down either MPL/TpoR or JAK2 in megakaryocytic progenitors from patients carrying CALR mutations inhibited cytokine-independent megakaryocytic colony formation. Taken together, our study provides a novel signaling paradigm, whereby a mutated chaperone constitutively activates cytokine receptor signaling.
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