KRAB zinc finger proteins ZNF587/ZNF417 protect lymphoma cells from replicative stress-induced inflammation [CUT&Tag]

Heterochromatin loss and genetic instability enhance cancer progression by favoring clonal diversity, yet uncontrolled replicative stress leads to mitotic catastrophe and inflammatory responses promoting immune rejection. KRAB-containing zinc finger proteins (KZFPs) contribute to heterochromatin maintenance at transposable elements (TEs). Here, we describe how upregulation of a cluster of primate-specific KZFPs is associated with poor prognosis, increased copy number alterations, and suppression of immune responses in diffuse large B cell lymphoma (DLBCL). Depleting two of these KZFPs targeting evolutionarily recent TEs, ZNF587 and ZNF417, impairs proliferation of cells derived from DLBCL and several other tumor types. This correlates with heterochromatin redistribution, replicative stress, and cGAS-STING-mediated induction of an interferon/inflammatory response leading to enhanced susceptibility to macrophage-mediated phagocytosis, increased surface expression of HLA-I and presentation of a neo-immunopeptidome. Thus, cancer cells can subvert KZFPs to dampen TE-originating surveillance mechanisms, which likely facilitates clonal expansion, diversification, and immune evasion. Overall design: CUT & Tag for H3K9me3 and gH2AX performed on two shZNF587/417 and two control samples for each mark, 72h after lentiviral transduction.

异染色质丢失与基因组不稳定性可通过促进克隆多样性加速癌症进展，而失控的复制应激则会诱发有丝分裂灾难与炎症反应，进而推动免疫排斥。含KRAB结构域的锌指蛋白（KRAB-containing zinc finger proteins, KZFPs）可维持转座元件（transposable elements, TEs）区域的异染色质稳态。本研究阐明，一组灵长类特异性KZFPs的上调与弥漫性大B细胞淋巴瘤（diffuse large B cell lymphoma, DLBCL）的不良预后、拷贝数变异增加及免疫应答抑制显著相关。敲低其中两个靶向进化上较新转座元件的KZFPs——ZNF587与ZNF417，可抑制DLBCL及其他多种肿瘤来源细胞的增殖能力；该效应与异染色质重分布、复制应激及cGAS-STING介导的干扰素/炎症应答激活相关，最终使肿瘤细胞更易被巨噬细胞吞噬，上调HLA-I分子的表面表达，并促进新生免疫肽组的抗原呈递。综上，肿瘤细胞可通过劫持KZFPs以抑制转座元件介导的监视机制，这一过程或有助于克隆扩增、克隆多样化及免疫逃逸。实验整体设计：在慢病毒转导72小时后，针对H3K9me3与gH2AX两个组蛋白标记，分别对两组靶向ZNF587/417的短发夹RNA样本及两组对照样本开展CUT&Tag实验。