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Targeting RNA Polymerase I to boost Natural Killer cell anticancer activity in Multiple Myeloma.

ABSTRACT: Multiple Myeloma (MM) remains an incurable disease despite therapeutic advancements extending survival. Relapses driven by drug resistance and minimal residual disease underscore the need for novel treatment strategies. Natural Killer (NK) cells play a key role in MM immunity, yet their function is suppressed by inhibitory cytokines and metabolites from the tumor microenvironment. Developing anticancer drugs with immunomodulatory properties, such as enhancing tumor sensitivity to NK cell recognition, remains a critical challenge. MM cells exhibit high protein synthesis rates, making them vulnerable to proteostasis disruption. Dysregulated ribosome function and aberrant mRNA translation contribute to proteasome inhibitor resistance. RNA Polymerase I (RNA Pol I)-mediated rDNA transcription, the rate-limiting step in ribosome biogenesis (RiBi), is significantly upregulated in MM. Targeting rDNA transcription and inducing nucleolar stress response (NSR) presents a promising therapeutic approach, though its immunomodulatory role is not well understood. Our study examined two “first-in-class” RNA Pol I inhibitors, CX-5461 and BMH-21, which differentially regulate NK cell-activating and inhibitory ligand expression in MM. BMH-21 enhanced NK cell degranulation and increased IFN-γ and TNF-α secretion, demonstrating stronger immunostimulatory effects than CX-5461. Conversely, CX-5461 induced a significant DNA damage response (DDR) and senescence, leading to HLA-E upregulation and suppressing NK cell activity. Mechanistic analyses revealed that HLA-E presentation is governed by ATR/AKT/mTORC1/S6K signaling and Pioneer Round of Translation (PRT), linking its regulation to DDR. This effect was modulated by Lenalidomide and Panobinostat. Moreover, RNA Pol I inhibition enhanced Daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC) of NK cells against MM, uncovering novel immuno-mediated antitumor mechanisms.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298220 | GEO | 2025/07/23

REPOSITORIES: GEO

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Project description:In recent years, several small molecule cytotoxic drugs have been identified as potential inhibitors of ribosome biogenesis (Drygin et al., 2011; Peltonen et al., 2014a; Peltonen et al., 2014b). CX-5461 is one such drug that has also demonstrated anticancer potential for a wide range of malignancies (Bywater et al., 2012; Cornelison et al., 2017; Devlin et al., 2015; Drygin et al., 2011; Hald et al., 2019; Hein et al., 2017; Ismael et al., 2019; Lawrence et al., 2018; Lee et al., 2017; Negi and Brown, 2015; Taylor et al., 2019; Xu et al., 2017; Yan et al., 2017) (Haddach et al., 2012), and is presently under phase I trials for the treatment of both hematological cancers and solid tumours (Group, 2016; Khot et al., 2019). CX-5461 was initially characterized as an inhibitor of RNA Polymerase I (RPI/PolR1/PolI) that is responsible for the synthesis of the major ribosomal RNAs and the initial step in ribosome biogenesis (Drygin et al., 2011). Since RPI and its corresponding core transcription factors are dedicated to this task alone, they present ideal molecular targets by which to modulate ribosome biogenesis. However, the specificity of CX-5461 has been questioned and it has been suggested that this drug may also act by stabilizing DNA G-quadruplexes or by “poisoning” topoisomerase II (Topo II). Thus, the primary target of this drug and its mode of action are still in doubt. Here we used Deconvolution-ChIP-Seq in NIH3T3 and HEK293T cells treated for different times with CX-5461. The data show that the primary target of CX5461 is the initiation of ribosomal RNA gene (rDNA) transcription. CX-5461 blocks transcription initiation in vitro and in vivo by arresting RNA polymerase I (RPI/Pol1) within the preinitiation complex. In contrast to previous suggestions, CX-5461 does not effect recruitment of the TBP-TAF complex SL1 to the rDNA promoter, the recruitment of the initiation competent RPI-Rrn3 complex or ongoing transcription elongation, arguing against a role for G-quadruplex stabilization or topoisomerase II poisoning. Inhibition of transcription by CX-5461 is not reversible, the RPI-Rrn3 complex remains arrested in the preinitiation complex even after drug removal. This leads to nucleolar stress, extensive DNA damage and cell senescence. Our data show that the cytotoxicity of CX-5461 is the downstream result of the highly specific inhibition of rDNA transcription. The observation that this inhibition is irreversible will be important for the future design of chemotherapeutic strategies and the avoidance of drug resistance.

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Targeting RNA Polymerase I to boost Natural Killer cell anticancer activity in Multiple Myeloma.

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