Integrating resistance functions to predict response to induction chemotherapy in de novo acute myeloid leukemia

This study explored resistance functions and their interactions in de novo AML treated with the "7 + 3" induction regimen. 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. 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. In summary, 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. Patients with AML who completed their “7+3” induction chemotherapy at Taichung Veterans General Hospital (TCVGH) were enrolled. We analyzed bone marrow samples from 52 patients with de novo AML who completed the “7+3” induction chemotherapy. These 52 patients were further referred to as the CR group (n = 35) and non-CR group (n = 17), respectively, according to their treatment response after the “7+3” induction chemotherapy.

本研究探讨了接受“7+3”诱导化疗方案的初治急性髓系白血病（de novo AML）的耐药功能及其相互作用。我们对52例完成“7+3”方案的初治AML患者的全骨髓样本RNA测序（RNA-sequencing）表达谱进行了分析，并将患者分为完全缓解（CR）组（n=35）与非完全缓解（non-CR）组（n=17）。系统基因集分析结果显示，化学耐药性与mTOR（P<0.001）、myc（P<0.001）、线粒体氧化磷酸化（mitochondrial oxidative phosphorylation，OXPHOS）及干细胞性（stemness，P=0.002）均存在显著关联。上述功能在基因构成与活性评分方面相互独立。整合上述四种功能构建的模型对化学耐药性的预测效能（受试者工作特征曲线下面积=0.815）优于任一单一功能模型。此外，本研究提出的7基因评分系统与四功能模型显著相关（r=0.97；P<0.001），可用于预测“7+3”方案的化学耐药性。多变量分析显示，当7基因评分≥-0.027时（风险比：11.18；95%置信区间：2.06~60.65；P=0.005），该评分是诱导治疗失败的独立危险因素。综上，myc、线粒体氧化磷酸化、mTOR与干细胞性均与AML的化学耐药相关。对于预测为“7+3”方案难治的初治AML患者，需考虑采用“7+3”方案以外的治疗手段。
本研究纳入了台中荣民总医院（Taichung Veterans General Hospital, TCVGH）收治的完成“7+3”诱导化疗的AML患者。我们分析了52例完成“7+3”诱导化疗的初治AML患者的骨髓样本。根据“7+3”诱导化疗后的治疗反应，将这52例患者进一步分为CR组（n=35）与non-CR组（n=17）。