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. CUT & Tag for H3K9me3 and gH2AX performed on two shZNF587/417 and two control samples for each mark, 72h after lentiviral transduction.