Yu-Chiao Chiu1,2, Tzu-Hung Hsiao1, Jia-Rong Tsai3, Li-Ju Wang1,2, Tzu-Chieh Ho4, Shih-Lan Hsu1, Chieh-Lin Jerry Teng3,5,6. 1. Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan. 2. Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. 3. Division of Hematology/Medical Oncology, Department of Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. 4. Department of Biomedical Engineering, Columbia University, New York, NY, USA. 5. Department of Life Science, Tunghai University, Taichung, Taiwan. 6. Faculty of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Abstract
OBJECTIVES: This study explored resistance functions and their interactions in de novo AML treated with the "7 + 3" induction regimen. METHODS: We analyzed RNA-sequencing profiles of whole bone marrow samples from 52 de novo AML patients who completed the "7 + 3" regimen and stratified patients into CR (n = 35) and non-CR (n = 17) groups. RESULTS: A systematic gene set analysis revealed significant associations between chemoresistance and mTOR (P < .001), myc (P < .001), mitochondrial oxidative phosphorylation (P < .001), and stemness (P = .002). These functions were independent with regard to gene contents and activity scores. An integration of these four functions showed a prediction of chemoresistance (area under the receiver operating characteristic curve = 0.815) superior to that of each function alone. Moreover, our proposed seven-gene scoring system significantly correlated with the four-function model (r = .97; P < .001) to predict chemoresistance to the "7 + 3" regimen. On multivariate analysis, a seven-gene score of ≥-0.027 (hazard ratio: 11.18; 95% confidence interval: 2.06-60.65; P = .005) was an independent risk factor for induction failure. CONCLUSIONS: Myc, OXPHOS, mTOR, and stemness were responsive for chemoresistance in AML. Treatments other than the "7 + 3" regimen need to be considered for de novo AML patients predicted to be refractory to the "7 + 3" regimen.
OBJECTIVES: This study explored resistance functions and their interactions in de novo AML treated with the "7 + 3" induction regimen. METHODS: We analyzed RNA-sequencing profiles of whole bone marrow samples from 52 de novo AMLpatients who completed the "7 + 3" regimen and stratified patients into CR (n = 35) and non-CR (n = 17) groups. RESULTS: A systematic gene set analysis revealed significant associations between chemoresistance and mTOR (P < .001), myc (P < .001), mitochondrial oxidative phosphorylation (P < .001), and stemness (P = .002). These functions were independent with regard to gene contents and activity scores. An integration of these four functions showed a prediction of chemoresistance (area under the receiver operating characteristic curve = 0.815) superior to that of each function alone. Moreover, our proposed seven-gene scoring system significantly correlated with the four-function model (r = .97; P < .001) to predict chemoresistance to the "7 + 3" regimen. On multivariate analysis, a seven-gene score of ≥-0.027 (hazard ratio: 11.18; 95% confidence interval: 2.06-60.65; P = .005) was an independent risk factor for induction failure. CONCLUSIONS:Myc, OXPHOS, mTOR, and stemness were responsive for chemoresistance in AML. Treatments other than the "7 + 3" regimen need to be considered for de novo AMLpatients predicted to be refractory to the "7 + 3" regimen.