Deregulation of transcription factors (TFs) leading to uncontrolled proliferation of tumor cells within the microenvironment represents a hallmark of cancer. However, the biological and clinical impact of transcriptional interference, particularly in multiple myeloma (MM) cells, remains poorly understood. The present study shows for the first time that MYC and JUNB, two crucial TFs implicated in MM pathogenesis, orchestrate distinct transcriptional programs. Specifically, our data revealed that expression levels of MYC, JUNB, and their respective downstream targets do not correlate and that their global chromatin-binding patterns are not significantly overlapping. Mechanistically, MYC expression was not affected by JUNB knockdown, and conversely, JUNB expression and transcriptional activity were not affected by MYC knockdown. Moreover, suppression of MYC levels in MM cells via targeting the master regulator BRD4 by either siRNA-mediated knockdown or treatment with the novel proteolysis targeting chimera (PROTAC) MZ-1 overcame bone marrow (BM) stroma cell/IL-6-induced MYC- but not MEK-dependent JUNB-upregulation and transcriptional activity. Consequently, targeting of the two non-overlapping MYC- and JUNB-transcriptoms by MZ-1 in combination with genetic or pharmacological JUNB-targeting approaches synergistically enhanced MM cell death, both in 2D and our novel dynamic 3D models of the BM milieu as well as in murine xenografts. In summary, our data emphasize the opportunity to employ MYC and JUNB dual-targeting treatment strategies in MM as another exciting approach to further improve patient outcomes.
转录因子（TFs）失调导致肿瘤细胞在微环境中不受控制地增殖是癌症的典型特征。然而，转录干扰的生物学和临床影响，尤其是在多发性骨髓瘤（MM）细胞中的作用，目前仍知之甚少。本研究首次揭示，MYC和JUNB这两个与MM发病机制密切相关的关键转录因子，各自调控不同的转录程序。具体而言，我们的数据显示，MYC和JUNB的表达水平及其各自下游靶点之间并无相关性，且两者的全基因组染色质结合模式也显著不重叠。从机制上看，JUNB敲低不影响MYC表达，反之，MYC敲低也不影响JUNB的表达和转录活性。此外，通过siRNA介导的敲低或新型蛋白水解靶向嵌合体（PROTAC）MZ-1靶向主调控因子BRD4来抑制MM细胞中的MYC水平，可以克服骨髓（BM）基质细胞/IL-6诱导的MYC依赖性上调，但未能抑制MEK依赖的JUNB上调及其转录活性。因此，在BM环境的二维模型、我们新型的动态三维模型以及小鼠异种移植模型中，MZ-1靶向非重叠的MYC和JUNB转录组，结合遗传或药理学靶向JUNB的策略，可协同增强MM细胞死亡。总之，我们的研究强调了在多发性骨髓瘤中采用MYC和JUNB双靶向治疗策略的潜力，这是进一步改善患者预后的又一振奋人心的途径。
肿瘤(癌症)患者之家