Targeting HASPIN kinase disrupts SR protein-mediated RNA splicing and synergizes with BCL-2 inhibitor venetoclax in AML
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PROVIDER: PRJNA1183348 | ENA |
REPOSITORIES: ENA
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Project description:Natural killer (NK) cell-based immunotherapy holds promise for cancer treatment, but its efficacy is still limited, necessitating the development of new strategies. Here, we report an unexpected discovery that venetoclax, the first FDA-approved BCL-2 inhibitor, acts as an immunometabolic modulator to potentiate adoptive NK cell immunotherapy against acute myeloid leukemia (AML). Venetoclax directly activates human NK cells, boosting their cytotoxicity against AML both in vitro and in vivo, independent of BCL-2 inhibition. Venetoclax enhances NK cell binding avidity and lytic granule polarization during immunological synapse (IS) formation.Furthermore, venetoclax promotes mitochondrial respiration and ATP synthesis via the NF-κB pathway, facilitating IS formation and effector function in human NK cells.Our findings establish venetoclax as a multifaceted immunometabolic modulator that enhances NK cell function, providing new insights for augmenting NK cell-mediated cytotoxicity in cancer immunotherapy.
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Project description:Natural killer (NK) cell-based immunotherapy holds promise for cancer treatment, but its efficacy is still limited, necessitating the development of new strategies. Here, we report an unexpected discovery that venetoclax, the first FDA-approved BCL-2 inhibitor, acts as an immunometabolic modulator to potentiate adoptive NK cell immunotherapy against acute myeloid leukemia (AML). Venetoclax directly activates human NK cells, boosting their cytotoxicity against AML both in vitro and in vivo, independent of BCL-2 inhibition. Notably, we identify a distinct CD161low CD218b+ NK cell subpopulation exhibiting the most pronounced proportional increase and transcriptomic changes upon venetoclax treatment.Venetoclax enhances NK cell binding avidity and lytic granule polarization during immunological synapse (IS) formation.Furthermore, venetoclax promotes mitochondrial respiration and ATP synthesis via the NF-κB pathway, facilitating IS formation and effector function in human NK cells.Our findings establish venetoclax as a multifaceted immunometabolic modulator that enhances NK cell function, providing new insights for augmenting NK cell-mediated cytotoxicity in cancer immunotherapy.
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Project description:The BCL-2 family plays important roles in acute myeloid leukemia (AML) and Venetoclax, a selective BCL-2 inhibitor, has received FDA approval for treatment of AML. However, drug resistance ensues after prolonged treatment, highlighting the need for a greater understanding of the underlying mechanisms. Using a genome-wide CRISPR/Cas9 screen in human AML, we identified genes whose inactivation sensitizes AML blasts to Venetoclax. Genes involved in mitochondrial organization and function were significantly depleted throughout our screen, including the mitochondrial chaperonin CLPB. We demonstrated that CLPB is upregulated in human AML, it is further induced upon acquisition of Venetoclax resistance and its ablation sensitizes AML cells to Venetoclax. Mechanistically, CLPB maintains the mitochondrial cristae structure via its interaction with the cristae-shaping protein OPA1, whereas its loss promotes apoptosis by inducing cristae remodeling and mitochondrial stress responses. Overall, our data suggest that targeting mitochondrial architecture may provide a promising approach to circumvent Venetoclax resistance.
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Project description:Survival rates for children diagnosed with acute lymphoblastic leukemia (ALL) have drastically improved, but those carrying mutations in the Mixed Lineage Leukemia (MLL) gene continue to have a very poor prognosis. The most common MLL mutation in ALL is the t(4;11)(q21;q23) chromosome translocation that fuses MLL in frame with the AF4 gene producing MLL-AF4 and AF4-MLL fusion proteins. Previously, we showed that MLL-AF4 binds to the BCL-2 gene and directly activates it through DOT1L recruitment and increased H3K79me2/3 levels. We went on to show that MLL leukemias are particularly sensitive to treatment with the BCL-2 inhibitor venetoclax which synergizes with both standard chemotherapeutic agents as well as DOT1L inhibitors. Altered expression of other BCL-2 family members is a major cause of resistance to ventoclax, so here we perform a detalied analysis of MLL-AF4 regulation of the entire BCL-2 family. By measuring nascent RNA production, we find that of all the BCL-2 family genes, MLL-AF4 directly controls the transcription of both BCL-2 and MCL-1, but only BCL-2 shows a significant loss of steady state RNA levels. Interestingly however, both MCL-1 and BCL-XL protein levels are dependent on MLL-AF4 activity through an unknown and likely indirect mechanism. Finally, we analyze MLL-AF4 regulation of the BCL-2 gene in greater detail and using Capture C we identify a major BCL-2 specific enhancer consisting of two clusters of H3K27Ac. Loss of MLL-AF4 activity results in a reduction of H2K27Ac levels at the major BCL-2 enhancer, revealing a novel regulatory dependence on MLL-AF4 function at BCL-2.
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