Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
Institute of Pathology, University of Ulm, Ulm, Germany.
Leukemia. 2020 Mar;34(3):857-871. doi: 10.1038/s41375-019-0628-0. Epub 2019 Nov 12.
In addition to oncogenic MYC translocations, Burkitt lymphoma (BL) depends on the germinal centre (GC) dark zone (DZ) B cell survival and proliferation programme, which is characterized by relatively low PI3K-AKT activity. Paradoxically, PI3K-AKT activation facilitates MYC-driven lymphomagenesis in mice, and it has been proposed that PI3K-AKT activation is essential for BL. Here we show that the PI3K-AKT activity in primary BLs and BL cell lines does not exceed that of human non-neoplastic tonsillar GC DZ B cells. BLs were not sensitive to AKT1 knockdown, which induced massive cell death in pAKT DLBCL cell lines. Likewise, BL cell lines show low sensitivity to pan-AKT inhibitors. Moreover, hyper-activation of the PI3K-AKT pathway by overexpression of a constitutively active version of AKT (myrAKT) or knockdown of PTEN repressed the growth of BL cell lines. This was associated with increased AKT phosphorylation, NF-κB activation, and downregulation of DZ genes including the proto-oncogene MYB and the DZ marker CXCR4. In contrast to GCB-DLBCL, PTEN overexpression was tolerated by BL cell lines. We conclude that the molecular mechanisms instrumental to guarantee the survival of normal DZ B cells, including the tight regulation of the PTEN-PI3K-AKT axis, also operate in the survival/proliferation of BL.
除致癌性 MYC 易位外，伯基特淋巴瘤（BL）还依赖生发中心（GC）暗区（DZ）B 细胞的存活和增殖程序，其特征是 PI3K-AKT 活性相对较低。矛盾的是，PI3K-AKT 的激活促进了小鼠中 MYC 驱动的淋巴瘤发生，并且有人提出 PI3K-AKT 的激活对于 BL 是必需的。在这里，我们表明，原发性 BL 和 BL 细胞系中的 PI3K-AKT 活性不超过人类非肿瘤性扁桃体 GC DZ B 细胞。BL 对 AKT1 敲低不敏感，AKT1 敲低会诱导 pAKT DLBCL 细胞系中大量细胞死亡。同样，BL 细胞系对 pan-AKT 抑制剂的敏感性也较低。此外，通过过表达 AKT（myrAKT）的组成性激活形式或敲低 PTEN 来过度激活 PI3K-AKT 通路会抑制 BL 细胞系的生长。这与 AKT 磷酸化、NF-κB 激活以及 DZ 基因的下调有关，包括原癌基因 MYB 和 DZ 标记物 CXCR4。与 GCB-DLBCL 相反，PTEN 的过表达可被 BL 细胞系耐受。我们的结论是，保证正常 DZ B 细胞存活的分子机制，包括 PTEN-PI3K-AKT 轴的严格调节，也在 BL 的存活/增殖中起作用。
