Calreticulin Ins5 and Del52 mutations impair unfolded protein and oxidative stress responses in K562 cells expressing CALR mutants

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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

Standort
Deutsche Nationalbibliothek Frankfurt am Main
Umfang
Online-Ressource
Sprache
Englisch
Anmerkungen
Scientific reports. - 9, 1 (2019) , 10558, ISSN: 2045-2322

Klassifikation
Biowissenschaften, Biologie
Schlagwort
Myeloproliferatives Syndrom

Ereignis
Veröffentlichung
(wo)
Freiburg
(wer)
Universität
(wann)
2019
Urheber
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

DOI
10.1038/s41598-019-46843-z
URN
urn:nbn:de:bsz:25-freidok-1503215
Rechteinformation
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Letzte Aktualisierung
25.03.2025, 13:44 MEZ

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Beteiligte

  • 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
  • Universität

Entstanden

  • 2019

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