Unfolded protein response suppresses CEBPA by induction of calreticulin in acute myeloid leukaemia

Schardt, Julian A; Eyholzer, Marianne; Timchenko, Nikolai A; Mueller, Beatrice U; Pabst, Thomas (2010). Unfolded protein response suppresses CEBPA by induction of calreticulin in acute myeloid leukaemia. Journal of Cellular and Molecular Medicine, 14(6B), pp. 1509-0519. Bucharest (Romania): Wiley 10.1111/j.1582-4934.2009.00870.x

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The unfolded protein response (UPR) is triggered by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). The role of the UPR during leukemogenesis is unknown so far. Here, we studied the induction of mediators of the UPR in leukaemic cells of AML patients. Increased expression of the spliced variant of the X-box binding protein 1 (XBP1s) was detected in 17.4% (16 of 92) of AML patients. Consistent with activated UPR, this group also had increased expression of ER-resident chaperones such as the 78 kD glucose-regulated protein (GRP78) and of calreticulin. Conditional expression of calreticulin in leukaemic U937 cells was found to increase calreticulin binding to the CEBPA mRNA thereby efficiently blocking translation of the myeloid key transcription factor CEBPA and ultimately affecting myeloid differentiation. Consequently, leukaemic cells from AML patients with activated UPR and thus increased calreticulin levels showed in fact suppressed CEBPA protein expression. We identified two functional ER stress response elements (ERSE) in the calreticulin promoter. The presence of NFY and ATF6, as well as an intact binding site for YY1 within these ERSE motifs were essential for mediating sensitivity to ER stress and activation of calreticulin. Thus, we propose a model of the UPR being activated in a considerable subset of AML patients through induction of calreticulin along the ATF6 pathway, thereby ultimately suppressing CEBPA translation and contributing to the block in myeloid differentiation.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of General Internal Medicine (DAIM) > Clinic of General Internal Medicine > Centre of Competence for General Internal Medicine
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology

UniBE Contributor:

Müller, Beatrice Ursula and Pabst, Thomas

ISSN:

1582-1838

Publisher:

Wiley

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:07

Last Modified:

03 May 2014 16:14

Publisher DOI:

10.1111/j.1582-4934.2009.00870.x

PubMed ID:

19659458

Web of Science ID:

000292023100013

URI:

https://boris.unibe.ch/id/eprint/102 (FactScience: 195881)

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