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Ref Type Journal Article
PMID (26668133)
Authors Chachoua I, Pecquet C, El-Khoury M, Nivarthi H, Albu RI, Marty C, Gryshkova V, Defour JP, Vertenoeil G, Ngo A, Koay A, Raslova H, Courtoy PJ, Choong ML, Plo I, Vainchenker W, Kralovics R, Constantinescu SN
Title Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants.
Journal Blood
Vol 127
Issue 10
Date 2016 Mar 10
URL
Abstract Text 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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
CALR K385fs frameshift gain of function CALR K385fs (reported as K385fs*47) results in a change in the amino acid sequence of the Calr protein beginning at aa 385 of 417, likely resulting in premature truncation of the functional protein (UniProt.org). K385fs confers a gain of function to Calr, as indicated by activation of JAK-STAT signaling and is transforming in cell culture (PMID: 26817954, PMID: 26987905, PMID: 26668133).
CALR K385Nfs*47 frameshift gain of function CALR K385Nfs*47 indicates a shift in the reading frame starting at amino acid 385 and terminating 47 residues downstream, resulting in premature truncation of the functional protein and extension of the 417aa Calr protein length by 15 amino acids (UniProt.org). K385Nfs*47 (reported as K385fs*47) results in activation of JAK-STAT signaling and is transforming in cell culture (PMID: 26817954, PMID: 26987905, PMID: 26668133).
CALR L367Tfs*46 frameshift gain of function CALR L367Tfs*46 indicates a shift in the reading frame starting at amino acid 367 and terminating 46 residues downstream causing a premature truncation of the 417 amino acid Calr protein (UniProt.org). L367Tfs*46 (reported as L367fs*46) results in activation of Jak-Stat signaling, is transforming in culture, and drives myeloproliferative neoplasm formation in animal models (PMID: 26668133, PMID: 26951227).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
CALR K385fs hematologic cancer sensitive Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) inhibited growth of transformed cells expressing CALR L385fs in culture (PMID: 26668133). 26668133
CALR L367fs hematologic cancer sensitive Ruxolitinib + Temsirolimus Preclinical - Cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) and Torisel (temsirolimus) acted synergistically to inhibit growth of transformed cells expressing CALR L367fs in culture (PMID: 26668133). 26668133
CALR L367fs hematologic cancer sensitive Ruxolitinib Preclinical - Cell culture Actionable In a preclinical study, Jakafi (ruxolitinib) inhibited growth of transformed cells expressing CALR L367fs in culture (PMID: 26668133). 26668133