Abstract：
The combination of venetoclax (VEN) and azacitidine (AZA) has become the standard of care for acute myeloid leukemia (AML) patients who are ≥ 75 years or unfit for intensive chemotherapy. Though initially promising, resistance to the combination therapy is an issue and VEN + AZA-relapsed/refractory patients have dismal outcomes. To better understand the mechanisms of resistance, we developed VEN + AZA-resistant AML cell lines, MV4-11/VEN + AZA-R and ML-2/VEN + AZA-R, which show > 300-fold persistent resistance compared to the parental lines. We demonstrate that these cells have unique metabolic profiles, including significantly increased levels of cytidine triphosphate (CTP) and deoxycytidine triphosphate (dCTP), changes in fatty acid and amino acid metabolism and increased utilization and reliance on glycolysis. Furthermore, fatty acid transporter CD36 is increased in the resistant cells compared to the parental cells. Inhibition of glycolysis with 2-Deoxy-D-glucose re-sensitized the resistant cells to VEN + AZA. In addition, the VEN + AZA-R cells have increased levels of the antiapoptotic protein Mcl-1 and decreased levels of the pro-apoptotic protein Bax. Overexpression of Mcl-1 or knockdown of Bax result in resistance to VEN + AZA. Our results provide insight into the molecular mechanisms contributing to VEN + AZA resistance and assist in the development of novel therapeutics to overcome this resistance in AML patients.
摘要：
维奈托克（VEN）和阿扎胞苷（AZA）的组合已成为≥75岁或不适合进行强化化疗的急性髓细胞性白血病（AML）患者的治疗标准。虽然最初很有希望，对联合治疗的耐药是一个问题,VEN+AZA-复发/难治性患者的预后不佳.为了更好地理解抗药性的机制，我们开发了抗VEN+AZA的AML细胞系,MV4-11/VEN+AZA-R和ML-2/VEN+AZA-R，与亲本系相比，其显示>300倍的持久性抗性。我们证明这些细胞具有独特的代谢谱，包括三磷酸胞苷（CTP）和三磷酸脱氧胞苷（dCTP）的水平显着增加，脂肪酸和氨基酸代谢的变化以及对糖酵解的利用和依赖增加。此外，脂肪酸转运蛋白CD36在抗性细胞中与亲本细胞相比增加。用2-脱氧-D-葡萄糖抑制糖酵解使抗性细胞对VEN+AZA重新敏感。此外,VEN+AZA-R细胞的抗凋亡蛋白Mcl-1水平升高,促凋亡蛋白Bax水平降低。Mcl-1的过表达或Bax的敲低导致对VEN+AZA的抗性。我们的结果提供了对VENAZA耐药性的分子机制的见解，并有助于开发新疗法以克服AML患者的这种耐药性。
