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.
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 AMLpatients. Consistent with activated unfolded protein response, this group also had significantly increased expression of calreticulin, GRP78, and CHOP. AMLpatients 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 AMLpatients 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 AMLpatients. AMLpatients with activated unfolded protein response present specific clinical characteristics and a more favorable course of the disease.
Authors: D I Staquicini; S D'Angelo; F Ferrara; K Karjalainen; G Sharma; T L Smith; C A Tarleton; D E Jaalouk; A Kuniyasu; W B Baze; B K Chaffee; P W Hanley; K F Barnhart; E Koivunen; S Marchiò; R L Sidman; J E Cortes; H M Kantarjian; W Arap; R Pasqualini Journal: Pharmacogenomics J Date: 2017-12-05 Impact factor: 3.550
Authors: C Zhou; E Martinez; D Di Marcantonio; N Solanki-Patel; T Aghayev; S Peri; F Ferraro; T Skorski; C Scholl; S Fröhling; S Balachandran; D L Wiest; S M Sykes Journal: Leukemia Date: 2016-11-14 Impact factor: 11.528
Authors: Padmaja Gade; Annique Wilson-Weekes; Rajasubramaniam Shanmugam; Hamid Sayar; Attaya Suvannasankha; Chirayu Goswami; Lang Li; Sushil Gupta; Angelo A Cardoso; Tareq Al Baghdadi; Katie J Sargent; Larry D Cripe; Dhananjaya V Kalvakolanu; H Scott Boswell Journal: Clin Cancer Res Date: 2011-11-17 Impact factor: 12.531