Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
Department of Physics and Astronomy, University of New Mexico, Albuquerque, NM, USA.
Oncogene. 2020 May;39(19):3910-3925. doi: 10.1038/s41388-020-1261-0. Epub 2020 Mar 19.
A principal challenge in treating acute myeloid leukemia (AML) is chemotherapy refractory disease. As such, there remains a critical need to identify key regulators of chemotherapy resistance in AML. In this study, we demonstrate that the membrane scaffold, CD82, contributes to the chemoresistant phenotype of AML. Using an RNA-seq approach, we identified the increased expression of the tetraspanin family member, CD82, in response to the chemotherapeutic, daunorubicin. Analysis of the TARGET and BEAT AML databases identifies a correlation between CD82 expression and overall survival of AML patients. Moreover, using a combination of cell lines and patient samples, we find that CD82 overexpression results in significantly reduced cell death in response to chemotherapy. Investigation of the mechanism by which CD82 promotes AML survival in response to chemotherapy identified a crucial role for enhanced protein kinase c alpha (PKCα) signaling and downstream activation of the β1 integrin. In addition, analysis of β1 integrin clustering by super-resolution imaging demonstrates that CD82 expression promotes the formation of dense β1 integrin membrane clusters. Lastly, evaluation of survival signaling following daunorubicin treatment identified robust activation of p38 mitogen-activated protein kinase (MAPK) downstream of PKCα and β1 integrin signaling when CD82 is overexpressed. Together, these data propose a mechanism where CD82 promotes chemoresistance by increasing PKCα activation and downstream activation/clustering of β1 integrin, leading to AML cell survival via activation of p38 MAPK. These observations suggest that the CD82-PKCα signaling axis may be a potential therapeutic target for attenuating chemoresistance signaling in AML.
治疗急性髓系白血病（AML）的一个主要挑战是化疗耐药疾病。因此，仍然迫切需要确定 AML 中化疗耐药的关键调节因子。在这项研究中，我们证明了膜支架 CD82 有助于 AML 的耐药表型。通过 RNA-seq 方法，我们发现四跨膜蛋白家族成员 CD82 的表达在化疗药物柔红霉素的作用下增加。对 TARGET 和 BEAT AML 数据库的分析表明，CD82 的表达与 AML 患者的总生存率之间存在相关性。此外，我们使用细胞系和患者样本的组合发现，CD82 的过表达导致对化疗的细胞死亡明显减少。研究 CD82 促进化疗时 AML 存活的机制发现，增强蛋白激酶 cα（PKCα）信号传导和下游β1 整合素激活起着至关重要的作用。此外，通过超分辨率成像分析 CD82 表达对β1 整合素募集的影响表明，CD82 表达促进了致密β1 整合素膜簇的形成。最后，在柔红霉素处理后评估存活信号发现，当 CD82 过表达时，PKCα 和β1 整合素信号下游的 p38 丝裂原激活蛋白激酶（MAPK）被强烈激活。总之，这些数据提出了一种机制，其中 CD82 通过增加 PKCα 的激活和下游β1 整合素的激活/募集来促进化疗耐药，从而通过激活 p38 MAPK 导致 AML 细胞存活。这些观察结果表明，CD82-PKCα 信号轴可能是减弱 AML 中化疗耐药信号的潜在治疗靶标。
