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.
Calreticulin Ins5 and Del52 mutations impair unfolded protein and oxidative stress responses in K562 cells expressing CALR mutants / Salati, Simona; Genovese, Elena; Carretta, Chiara; Zini, Roberta; Bartalucci, Niccolò; Prudente, Zelia; Pennucci, Valentina; Ruberti, Samantha; Rossi, Chiara; Rontauroli, Sebastiano; Enzo, Elena; Calabresi, Laura; Balliu, Manjola; Mannarelli, Carmela; Bianchi, Elisa; Guglielmelli, Paola; Tagliafico, Enrico; Vannucchi, Alessandro M; Manfredini, Rossella. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 9(2019), pp. 1-14. [10.1038/s41598-019-46843-z]
Data di pubblicazione: | 2019 | |
Titolo: | Calreticulin Ins5 and Del52 mutations impair unfolded protein and oxidative stress responses in K562 cells expressing CALR mutants | |
Autore/i: | Salati, Simona; Genovese, Elena; Carretta, Chiara; Zini, Roberta; Bartalucci, Niccolò; Prudente, Zelia; Pennucci, Valentina; Ruberti, Samantha; Rossi, Chiara; Rontauroli, Sebastiano; Enzo, Elena; Calabresi, Laura; Balliu, Manjola; Mannarelli, Carmela; Bianchi, Elisa; Guglielmelli, Paola; Tagliafico, Enrico; Vannucchi, Alessandro M; Manfredini, Rossella | |
Autore/i UNIMORE: | ||
Digital Object Identifier (DOI): | http://dx.doi.org/10.1038/s41598-019-46843-z | |
Rivista: | ||
Volume: | 9 | |
Pagina iniziale: | 1 | |
Pagina finale: | 14 | |
Codice identificativo ISI: | WOS:000476713900022 | |
Codice identificativo Scopus: | 2-s2.0-85070313676 | |
Codice identificativo Pubmed: | 31332222 | |
Citazione: | Calreticulin Ins5 and Del52 mutations impair unfolded protein and oxidative stress responses in K562 cells expressing CALR mutants / Salati, Simona; Genovese, Elena; Carretta, Chiara; Zini, Roberta; Bartalucci, Niccolò; Prudente, Zelia; Pennucci, Valentina; Ruberti, Samantha; Rossi, Chiara; Rontauroli, Sebastiano; Enzo, Elena; Calabresi, Laura; Balliu, Manjola; Mannarelli, Carmela; Bianchi, Elisa; Guglielmelli, Paola; Tagliafico, Enrico; Vannucchi, Alessandro M; Manfredini, Rossella. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 9(2019), pp. 1-14. [10.1038/s41598-019-46843-z] | |
Tipologia | Articolo su rivista |
File in questo prodotto:
File | Descrizione | Tipologia | |
---|---|---|---|
s41598-019-46843-z.pdf | Versione dell'editore (versione pubblicata) | Open Access Visualizza/Apri |
Pubblicazioni consigliate

I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris