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

异染色质丢失与遗传不稳定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引发有丝分裂灾难及介导免疫排斥的炎症反应。含KRAB结构域的锌指蛋白（KRAB-containing zinc finger proteins, KZFPs）可在转座因子（transposable elements, TEs）位点维持异染色质稳态。本研究揭示了一群灵长类特异性KZFPs的上调与弥漫性大B细胞淋巴瘤（diffuse large B cell lymphoma, DLBCL）患者的不良预后、拷贝数变异增多以及免疫应答受抑显著相关。靶向进化上较新TEs的其中两种KZFPs——ZNF587与ZNF417——的敲低，会削弱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、复制应激以及cGAS-STING介导的干扰素/炎症反应诱导密切相关；这一反应可增强细胞对巨噬细胞介导的吞噬作用的敏感性，上调人类白细胞抗原I类（HLA-I）分子的表面表达，并促进新免疫肽组（neo-immunopeptidome）的呈递。由此可见，肿瘤细胞可通过劫持KZFPs以抑制TE来源的监视机制，这一过程可能有助于克隆扩增、克隆多样化以及免疫逃逸。实验整体设计：在慢病毒转染72小时后，针对组蛋白H3赖氨酸9三甲基化（H3K9me3）与磷酸化组蛋白H2AX（gH2AX）两个标记物，分别对2份shZNF587/417样本及2份对照样本开展CUT&Tag检测。