Targeting RNA Polymerase I to boost Natural Killer cell anticancer activity in Multiple Myeloma.
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ABSTRACT:
PROVIDER: PRJNA1268533 | ENA |
REPOSITORIES: ENA
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Project description: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.
2025-07-23 | GSE298220 | GEO
Project description:Conventional natural killer (NK)-based anticancer immunotherapy has a limitation in that a culture period of approximately 2 weeks is required to increase the number and activity of NK cells. In addition, the anticancer activity of NK cells is closely associated with their mitochondrial function. In this study, we aimed to investigate whether the NK-anticancer activity increased after transferring allogeneic mitochondria into NK cells. Using this method, NK cells with enhanced anticancer activity can be produced without in vitro culture and can be used for anticancer treatment.
2024-01-22 | GSE224187 | GEO
Project description:Natural Killer cells (NK), a major constituent of innate immune system, have the ability to kill the transformed and infected cells without prior sensitization; can be put to immunotherapeutic use against various malignancies. NK cells discriminate between normal cells and transformed cells via a balance of inhibitory and activating signals induced by interactions between NK cell receptors and target cell ligands. Present study investigates whether expansion of NK cells could augment their anti-myeloma (MM) activity. For NK cell expansion, peripheral blood mononuclear cells from healthy donors and myeloma patients were co-cultured with irradiated K562 cells transfected with 4-1BBL and membrane-bound IL15 (K562-mb15-41BBL). A genome-wide profiling approach was performed to identify gene expression signature in expanded NK (ENK) cells and non-expanded NK cells isolated from healthy donors and myeloma patients. A specific set of genes involved in proliferation, migration, adhesion, cytotoxicity, and activation were up regulated post expansion, also confirmed by flow cytometry. Exp-NK cells killed both allogeneic and autologous primary MM cells more avidly than non-exp-NK cells in vitro. Multiple receptors, particularly NKG2D, natural cytotoxicity receptors, and DNAM-1 contributed to target lysis, via a perforin mediated mechanism. In summary, vigorous expansion and high anti-MM activity both in vitro and in vivo provide the rationale for testing exp-NK cells in a clinical trial for high risk MM. Differential gene expression profile in expanded natural killer (ENK) cells and non-expanded natural killer (NK) cells from healthy donors and myeloma patients Eight healthy donor and eight myeloma patients were used in the study. Non-expanded natural killer (NK) cells were isolated from PBMCs of healthy donors and myeloma patients. Expanded natural killer (ENK) cells were generated from same set of samples as mentioned in expansion protocol. All ENK and NK cells were used for gene expression profiling.
2011-03-08 | E-GEOD-27838 | biostudies-arrayexpress
Project description:Natural Killer cells (NK), a major constituent of innate immune system, have the ability to kill the transformed and infected cells without prior sensitization; can be put to immunotherapeutic use against various malignancies. NK cells discriminate between normal cells and transformed cells via a balance of inhibitory and activating signals induced by interactions between NK cell receptors and target cell ligands. Present study investigates whether expansion of NK cells could augment their anti-myeloma (MM) activity. For NK cell expansion, peripheral blood mononuclear cells from healthy donors and myeloma patients were co-cultured with irradiated K562 cells transfected with 4-1BBL and membrane-bound IL15 (K562-mb15-41BBL). A genome-wide profiling approach was performed to identify gene expression signature in expanded NK (ENK) cells and non-expanded NK cells isolated from healthy donors and myeloma patients. A specific set of genes involved in proliferation, migration, adhesion, cytotoxicity, and activation were up regulated post expansion, also confirmed by flow cytometry. Exp-NK cells killed both allogeneic and autologous primary MM cells more avidly than non-exp-NK cells in vitro. Multiple receptors, particularly NKG2D, natural cytotoxicity receptors, and DNAM-1 contributed to target lysis, via a perforin mediated mechanism. In summary, vigorous expansion and high anti-MM activity both in vitro and in vivo provide the rationale for testing exp-NK cells in a clinical trial for high risk MM. Differential gene expression profile in expanded natural killer (ENK) cells and non-expanded natural killer (NK) cells from healthy donors and myeloma patients
2011-03-08 | GSE27838 | GEO
Project description:Enhancement of the anticancer ability of natural killer cells through allogeneic mitochondrial transfer
| PRJNA930031 | ENA
Project description:Natural killer (NK) cells support the anti-myeloma activity of daratumumab via antibody-dependent cellular cytotoxicity (ADCC) in multiple myeloma (MM). However, the different roles of heterogeneous NK cell subpopulations have not been elucidated in MM. Here, we delineate memory-like NK cells in the bone marrow (BM) of newly diagnosed MM (NDMM) patients using single-cell RNA sequencing, and further characterize their distinct immunophenotypic features and functions by multicolor flow cytometry. Memory-like NK cells exert robust daratumumab-mediated effector functions ex vivo, including cytokine production and degranulation, compared to conventional NK cells. The composition of memory-like NK cells in BM determines the daratumumab-mediated ex vivo functional activity of BM NK cells in NDMM patients. Unlike conventional NK cells, sorted memory-like NK cells from the BM of NDMM patients exert substantial cytotoxic activity against myeloma cells in the presence of daratumumab. Our findings indicate that memory-like NK cells are an important mediator of daratumumab-dependent effector functions in MM and support direct future efforts to better predict and improve the clinical efficacy of therapeutic antibodies by selectively employing memory-like NK cells.
2021-08-01 | GSE155795 | GEO
Project description:Investigation of global gene expression levels between B cells, Natural killer cells and Natural killer B cells Gene expression profiling using sorted B cells, Natural killer cells and Natural killer B cells from WT mouse spleen. Total RNA extracted from WT cells were quantified by the NanoDrop ND-1000 and RNA integrity was assessed by standard denaturing agarose gel electrophoresis. The sample preparation and microarray hybridization were performed based on the NimbleGenâs standard protocols.
2016-05-17 | E-GEOD-80063 | biostudies-arrayexpress
Project description:Memory-like natural killer cells facilitate effector functions of daratumumab in multiple myeloma
| PRJNA658903 | ENA
Project description:Comparing global gene expression of neonatal and adult natural killer cells to determine if differences in gene expression suggest that different developmental pathways during hematopoiesis are followed in the fetal and adult mouse to produce mature natural killer cells.
2005-10-01 | E-MEXP-354 | biostudies-arrayexpress
Project description:Investigation of global gene expression levels between B cells, Natural killer cells and Natural killer B cells
2016-05-17 | GSE80063 | GEO