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| Status |
Public on Aug 20, 2020 |
| Title |
Calreticulin Ins5 and Del52 mutations impair unfolded protein and oxidative stress responses in hematopoietic cells |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Somatic mutations of calreticulin (CALR) have been described in approximately 30-40% of JAK2 and MPL unmutated essential trombocytemia and primary myelofibrosis patients. CALR is a chaperone that localizes primarily in the endoplasmic reticulum (ER) where it is responsible for the control of proper protein folding and for the calcium retention. Recent data have 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 attempted to clarify whether CALR mutations may affect the functions of CALR in the ER under homeostatic conditions. Our results 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, therefore allowing the accumulation of unfolded proteins and conferring resistance to ER-stress induced apoptosis. Moreover, our data demonstrated that CALR mutations induce increased sensitivity to oxidative stress, reducing the ability to counteract ROS intracellular accumulation and thus 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 CALR mutations. Altogether, our data identify a novel MPL-independent mechanism involved in the development of MPNs mediated by CALR mutants: CALR mutations negatively impact on the capability of cells to respond to oxidative stress, and this in turn leads to increase DNA damage and genomic instability.
We used microarrays to detail the change of gene expression caused by calreticulin mutations in K562 cells
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| Overall design |
K562 cells were transduced with CALR wt, CARLIns5 and CALR Del52 respectively and analyzed for gene expression .
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| Contributor(s) |
Salati S, Manfredini R |
| Citation missing |
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| |
| Submission date |
Aug 21, 2017 |
| Last update date |
Jul 25, 2021 |
| Contact name |
Rossella Manfredini |
| E-mail(s) |
[email protected]
|
| Phone |
+390592058065
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| Organization name |
Centre for Regenerative Medicine
|
| Department |
Life Sciences
|
| Street address |
Via Gottardi 100
|
| City |
Modena |
| ZIP/Postal code |
41100 |
| Country |
Italy |
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| Platforms (1) |
| GPL13667 |
[HG-U219] Affymetrix Human Genome U219 Array |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA399186 |
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