Wang Jinfen, Xu-Monette Zijun Y, Jabbar Kausar J, Shen Qi, Manyam Ganiraju C, Tzankov Alexandar, Visco Carlo, Wang Jing, Montes-Moreno Santiago, Dybkær Karen, Tam Wayne, Bhagat Govind, Hsi Eric D, van Krieken J Han, Ponzoni Maurilio, Ferreri Andrés J M, Wang Shi, Møller Michael B, Piris Miguel A, Medeiros L Jeffrey, Li Yong, Pham Lan V, Young Ken H
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Pathology, Shanxi Cancer Hospital, Shanxi, China.
Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Am J Pathol. 2017 Aug;187(8):1700-1716. doi: 10.1016/j.ajpath.2017.04.009. Epub 2017 Jun 13.
AKT signaling is important for proliferation and survival of tumor cells. The clinical significance of AKT activation in diffuse large B-cell lymphoma (DLBCL) is not well analyzed. Here, we assessed expression of phosphorylated AKT (p-AKT) in 522 DLBCL patients. We found that high levels of p-AKT nuclear expression, observed in 24.3% of the study cohort, were associated with significantly worse progression-free survival and Myc and Bcl-2 overexpression. However, multivariate analysis indicated that AKT hyperactivation was not an independent factor. miRNA profiling analysis demonstrated that 63 miRNAs directly or indirectly related to the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway were differentially expressed between DLBCLs with high and low p-AKT nuclear expression. We further targeted AKT signaling using a highly selective AKT inhibitor MK-2206 in 26 representative DLBCL cell lines and delineated signaling alterations using a reverse-phase protein array. MK-2206 treatment inhibited lymphoma cell viability, and MK-2206 sensitivity correlated with AKT activation status in DLBCL cells. On MK-2206 treatment, p-AKT levels and downstream targets of AKT signaling were significantly decreased, likely because of the decreased feedback repression; Rictor and phosphatidylinositol 3-kinase expression and other compensatory pathways were also induced. This study demonstrates the clinical and therapeutic implications of AKT hyperactivation in DLBCL and suggests that AKT inhibitors need to be combined with other targeted agents for DLBCL to achieve optimal clinical efficacy.
AKT信号传导对肿瘤细胞的增殖和存活至关重要。AKT激活在弥漫性大B细胞淋巴瘤（DLBCL）中的临床意义尚未得到充分分析。在此，我们评估了522例DLBCL患者中磷酸化AKT（p-AKT）的表达。我们发现，在24.3%的研究队列中观察到的高水平p-AKT核表达与无进展生存期显著较差以及Myc和Bcl-2过表达相关。然而，多变量分析表明AKT过度激活不是一个独立因素。miRNA谱分析表明，在p-AKT核表达高和低的DLBCL之间，63种与磷脂酰肌醇3-激酶/AKT/雷帕霉素作用机制靶点通路直接或间接相关的miRNA存在差异表达。我们在26种代表性DLBCL细胞系中使用高度选择性AKT抑制剂MK-2206靶向AKT信号传导，并使用反相蛋白质阵列描绘信号改变。MK-2206处理抑制淋巴瘤细胞活力，且MK-2206敏感性与DLBCL细胞中的AKT激活状态相关。在MK-2206处理后，p-AKT水平和AKT信号传导的下游靶点显著降低，可能是由于反馈抑制降低；Rictor和磷脂酰肌醇3-激酶表达以及其他补偿途径也被诱导。本研究证明了AKT过度激活在DLBCL中的临床和治疗意义，并表明AKT抑制剂需要与其他靶向药物联合用于DLBCL以实现最佳临床疗效。
