Gene expression analysis of EuMyc lymphoma cells after MYC inactivation

Tumors that overexpress the MYC oncogene frequently demonstrate aneuploidy, numerical chromosome alterations associated with highly aggressive cancers, rapid tumor evolution, and poor patient outcome. Here, we identify that MYC overexpression induces defects in microtubule nucleation and mitotic spindle assembly, promoting chromosome segregation defects, micronuclei and chromosomal instability (CIN). High TPX2 expression is permissive for mitotic spindle assembly and chromosome segregation in cells with MYC overexpression; whereas TPX2 depletion blocks mitotic progression, induces cell death and prevents tumor growth. Attenuating MYC expression reverses mitotic defects, even in established tumor cell lines, implicating an ongoing role for high MYC in the persistence of CIN in tumors. Our studies implicate the MYC oncogene as a regulator of spindle assembly and identify a new MYC-TPX2 synthetic-lethal interaction that could represent a future therapeutic strategy in MYC-overexpressing cancers. Moreover, our studies suggest that blocking MYC activity can attenuate the emergence of CIN and tumor evolution. Cells were grown in the absence (MYC ON, reference samples) of doxycycline and presence of doxycycline for three days (MYC OFF). Three biological replicates of each condition were performed.

过表达MYC癌基因（MYC oncogene）的肿瘤常表现出非整倍体（aneuploidy）——一类与高侵袭性癌症、快速肿瘤演进及患者不良预后密切相关的染色体数目异常。本研究发现，MYC过表达会诱导微管成核（microtubule nucleation）与有丝分裂纺锤体组装（mitotic spindle assembly）缺陷，进而引发染色体分离缺陷、微核（micronuclei）及染色体不稳定性（chromosomal instability, CIN）。TPX2（TPX2）高表达可使过表达MYC的细胞维持有丝分裂纺锤体组装与染色体分离过程；而敲低TPX2则会阻断有丝分裂进程、诱导细胞死亡并抑制肿瘤生长。即便在已建立的肿瘤细胞系中，减弱MYC表达也可逆转有丝分裂缺陷，这表明高表达MYC在肿瘤染色体不稳定性（CIN）的维持中发挥着持续作用。本研究证实MYC癌基因可作为纺锤体组装的调控因子，并发现了一种全新的MYC-TPX2合成致死（synthetic-lethal）互作关系，该互作有望成为针对MYC过表达癌症的未来治疗策略。此外，本研究还表明，抑制MYC活性可减弱染色体不稳定性（CIN）的产生及肿瘤演进过程。实验细胞分别在不添加多西环素（MYC激活组，即对照样本）与添加多西环素并培养三天（MYC抑制组）的条件下培养；每种处理条件均设置三次生物学重复。