Activation of the unfolded protein response is associated with favorable prognosis in acute myeloid leukemia

Schardt, Julian A; Weber, Daniel; Eyholzer, Marianne; Mueller, Beatrice U; Pabst, Thomas (2009). Activation of the unfolded protein response is associated with favorable prognosis in acute myeloid leukemia. Clinical cancer research, 15(11), pp. 3834-41. Philadelphia, Pa.: American Association for Cancer Research 10.1158/1078-0432.CCR-08-2870

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PURPOSE: The unfolded protein response is triggered by the accumulation of misfolded proteins within the endoplasmic reticulum. Previous studies suggest that the unfolded protein response is activated in some cancer cell lines and involved in tumor development. The role of the unfolded protein response during leukemogenesis is unknown thus far. EXPERIMENTAL DESIGN: Here, we assessed the induction of key effectors of the unfolded protein response in leukemic cells at diagnosis of 105 acute myeloid leukemia (AML) patients comprising all subtypes. We determined the formation of the spliced variant of the X-box-binding protein 1 (XBP1) mRNA, as well as expression levels of calreticulin, GRP78, and CHOP mRNA. RESULTS: The formation of the spliced variant of XBP1s was detectable in 16.2% (17 of 105) of AML patients. Consistent with activated unfolded protein response, this group also had significantly increased expression of calreticulin, GRP78, and CHOP. AML patients with activated unfolded protein response had lower WBC counts, lactate dehydrogenase levels, and more frequently, secondary AML. The incidence of fms-related tyrosine kinase 3 (FLT3) mutations was significantly lower in patients with activated unfolded protein response. In addition, an association was observed between activated unfolded protein response and deletion of chromosome 7. Finally, the clinical course of AML patients with activated unfolded protein response was more favorable with lower relapse rate (P = 0.0182) and better overall (P = 0.041) and disease-free survival (P = 0.022). CONCLUSIONS: These results suggest that the unfolded protein response is activated in a considerable subset of AML patients. AML patients with activated unfolded protein response present specific clinical characteristics and a more favorable course of the disease.

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, Pabst, Thomas Niklaus
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 15:11
Last Modified:	02 Mar 2023 23:23
Publisher DOI:	10.1158/1078-0432.CCR-08-2870
PubMed ID:	19470730
Web of Science ID:	000266659000023
URI:	https://boris.unibe.ch/id/eprint/31385 (FactScience: 195882)