Lopez-Millan Belen, Diaz de la Guardia Rafael, Roca-Ho Heleia, Anguita Eduardo, Islam Abul B M M K, Romero-Moya Damia, Prieto Cristina, Gutierrez-Agüera Francisco, Bejarano-Garcia Jose Antonio, Perez-Simon Jose Antonio, Costales Paula, Rovira Montse, Marín Pedro, Menendez Silvia, Iglesias Mar, Fuster Jose Luis, Urbano-Ispizua Alvaro, Anjos-Afonso Fernando, Bueno Clara, Menendez Pablo
Department of Biomedicine, Josep Carreras Leukemia Research Institute-Campus Clinic, School of Medicine, University of Barcelona, Barcelona, Spain.
Hematology Department, Hospital Clínico San Carlos, IdISSC, Universidad Complutense de Madrid, Madrid, Spain.
Oncoimmunology. 2018 Jul 26;7(9):e1477460. doi: 10.1080/2162402X.2018.1477460. eCollection 2018.
Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk between AML cells and the BM stroma is a major mechanism underlying therapy resistance in AML. Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma. Whether IMiDs may improve the efficacy of current standard treatment in AML remains understudied. Here, we have exploited and preclinical AML models to analyze whether IMiDs potentiate the efficacy of AraC/Idarubicin-based standard AML chemotherapy by interfering with the BM stroma-mediated chemoresistance. We report that IMiDs do not exert cytotoxic effects on either non-del5q/5q- AML cells nor BM-MSCs, but they enhance the immunomodulatory properties of BM-MSCs. When combined with AraC/Idarubicin, IMiDs fail to circumvent BM stroma-mediated resistance of non-del5q/5q- AML cells and but induce robust extramedullary mobilization of AML cells. When administered as a single agent, lenalidomide specifically mobilizes non-del5q/5q- AML cells, but not healthy CD34 cells, to peripheral blood (PB) through specific downregulation of CXCR4 in AML blasts. Global gene expression profiling supports a migratory/mobilization gene signature in lenalidomide-treated non-del5q/5q- AML blasts but not in CD34 cells. Collectively, IMiDs mobilize non-del5q/5q- AML blasts to PB through CXCR4 downregulation, but fail to potentiate AraC/Idarubicin activity in preclinical models of non-del5q/5q- AML.
急性髓系白血病（AML）的治疗效果仍不理想，许多患者在基于核苷类似物加蒽环类药物的标准化疗后仍难治或复发。AML细胞与骨髓基质之间的相互作用是AML治疗耐药的主要机制。来那度胺和泊马度胺是新一代免疫调节药物（IMiDs），具有多效抗白血病特性，包括强大的免疫调节作用，常用于与骨髓内在功能障碍相关的血液系统恶性肿瘤，如骨髓增生异常综合征和多发性骨髓瘤。IMiDs是否能提高AML当前标准治疗的疗效仍未得到充分研究。在此，我们利用临床前AML模型分析IMiDs是否通过干扰骨髓基质介导的化疗耐药性来增强基于阿糖胞苷/伊达比星的标准AML化疗的疗效。我们报告，IMiDs对非del5q/5q-AML细胞和骨髓间充质干细胞（BM-MSCs）均无细胞毒性作用，但它们增强了BM-MSCs的免疫调节特性。与阿糖胞苷/伊达比星联合使用时，IMiDs未能克服骨髓基质介导的非del5q/5q-AML细胞的耐药性，但可诱导AML细胞强大的髓外动员。当作为单一药物给药时，来那度胺通过特异性下调AML原始细胞中的CXCR4，将非del5q/5q-AML细胞而非健康的CD34细胞特异性动员至外周血（PB）。全基因组表达谱分析支持来那度胺处理的非del5q/5q-AML原始细胞中存在迁移/动员基因特征，但在CD34细胞中不存在。总体而言，IMiDs通过下调CXCR4将非del5q/5q-AML原始细胞动员至PB，但在非del5q/5q-AML临床前模型中未能增强阿糖胞苷/伊达比星的活性。
