Abstract
Somatic mutations of calreticulin (CALR) have been described in approximately 60–80% of JAK2 and MPL unmutated Essential Thrombocythemia and Primary Myelofibrosis patients. CALR is an endoplasmic reticulum (ER) chaperone responsible for proper protein folding and calcium retention. Recent data demonstrated that the TPO receptor (MPL) is essential for the development of CALR mutant-driven Myeloproliferative Neoplasms (MPNs). However, the precise mechanism of action of CALR mutants haven’t been fully unraveled. In this study, we showed that CALR mutants impair the ability to respond to the ER stress and reduce the activation of the pro-apoptotic pathway of the unfolded protein response (UPR). Moreover, our data demonstrated that CALR mutations induce increased sensitivity to oxidative stress, leading to increase oxidative DNA damage. We finally demonstrated that the downmodulation of OXR1 in CALR-mutated cells could be one of the molecular mechanisms responsible for the increased sensitivity to oxidative stress mediated by mutant CALR. Altogether, our data identify novel mechanisms collaborating with MPL activation in CALR-mediated cellular transformation. CALR mutants negatively impact on the capability of cells to respond to oxidative stress leading to genomic instability and on the ability to react to ER stress, causing resistance to UPR-induced apoptosis.
Highlights
Somatic mutations of calreticulin (CALR) have been described in approximately 60–80% of JAK2 and MPL unmutated Essential Thrombocythemia and Primary Myelofibrosis patients
Marty et al.[6] showed that CALR mutations are able to induce the development of an Essential Thrombocythemia (ET)-like phenotype in mice, whilst Chachoua et al demonstrated the requirement of the Thrombopoietin receptor (MPL) for CALR-mediated cellular transformation[7]
Since CALR has been demonstrated to be involved in endoplasmic reticulum (ER) and oxidative stress response in different cell types[11], here we investigated whether CALR mutations could be responsible for an abnormal response to ER and/or oxidative stress and whether this aberrant response could represent a pathogenetic mechanism cooperating with MPL activation in CALR-mediated cellular transformation
Summary
Somatic mutations of calreticulin (CALR) have been described in approximately 60–80% of JAK2 and MPL unmutated Essential Thrombocythemia and Primary Myelofibrosis patients. CALR is an endoplasmic reticulum (ER) chaperone responsible for proper protein folding and calcium retention. We showed that CALR mutants impair the ability to respond to the ER stress and reduce the activation of the pro-apoptotic pathway of the unfolded protein response (UPR). We demonstrated that the downmodulation of OXR1 in CALR-mutated cells could be one of the molecular mechanisms responsible for the increased sensitivity to oxidative stress mediated by mutant CALR. In 2013, two groups reported the discovery of mutations in the CALR gene in Myeloproliferative Neoplasms (MPNs), in 60–80% of JAK2 and MPL unmutated Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) patients[4,5]. The mutation has been detected in hematopoietic stem and progenitor cells and hierarchical clonal analyses showed early acquisition of the CALR mutation, consistent with its role as initiating event of the disease
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