Högstrand Kari, Darmanin Stephanie, Forshell TachaZi Plym, Grandien Alf
Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital-Huddinge, 141 57 Stockholm, Sweden.
Oncotarget. 2018 Apr 20;9(30):21396-21410. doi: 10.18632/oncotarget.25113.
Peripheral T-cell lymphoma is an aggressive non-Hodgkin's lymphoma characterized by excessive proliferation of transformed mature T cells. The number and nature of genetic aberrations required and sufficient for transformation of normal T cells into lymphomas is unknown. Here, using a combinatorial -approach, we demonstrate that overexpression of MYC together with activated AKT in conditions of inhibition of intrinsic apoptosis rapidly resulted in transformation of mature mouse T cells with a frequency approaching 100%. Injection of transformed cells into mice resulted in rapid development of aggressive T cell lymphoma, characterized by spread to several organs, destruction of tissue architecture and rapid death of the animals. TcR-sequencing revealed a polyclonal repertoire of tumor cells indicating that co-expression of MYC, activated AKT and BCLXL is sufficient for tumor transformation and do not require acquisition of additional genetic events. When analyzing cells with inducible expression we found that proliferation of transformed T cells required sustained expression of both MYC and AKT. AKT exerted a dual function as it inhibited induction of, and promoted exit from, cellular quiescence and contributed to inhibion of apoptosis. Downregulation of AKT and/or MYC together with BCLXL resulted in rapid and complete elimination of cells through induction of apoptotic cell death.
外周T细胞淋巴瘤是一种侵袭性非霍奇金淋巴瘤，其特征为转化成熟T细胞过度增殖。正常T细胞转化为淋巴瘤所需且足够的基因畸变的数量和性质尚不清楚。在此，我们采用组合方法证明，在抑制内源性凋亡的条件下，MYC的过表达与激活的AKT共同作用，能迅速导致成熟小鼠T细胞转化，频率接近100%。将转化细胞注射到小鼠体内会导致侵袭性T细胞淋巴瘤迅速发展，其特征为扩散至多个器官、组织结构破坏以及动物快速死亡。TcR测序显示肿瘤细胞具有多克隆谱系，表明MYC、激活的AKT和BCLXL的共表达足以实现肿瘤转化，且不需要获得额外的基因事件。在分析可诱导表达的细胞时，我们发现转化T细胞的增殖需要MYC和AKT的持续表达。AKT发挥双重功能，它抑制细胞静止的诱导并促进细胞从静止状态退出，同时有助于抑制凋亡。AKT和/或MYC与BCLXL一起下调会通过诱导凋亡性细胞死亡导致细胞迅速且完全清除。
