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Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML [ATACseq_MV4_11]

ABSTRACT: Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML [ATACseq_MV4_11]

PROVIDER: PRJNA1265509 | ENA |

REPOSITORIES: ENA

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Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML [ATACseq_MV4_11]

Project description:The heterogeneity of leukemic cells is the main cause of resistance to therapy in acute myeloid leukemia (AML). Consequently, innovative therapeutic approaches are critical to target a wide spectrum of leukemic clones, regardless of their genetic and non-genetic complexity. In this report, we leverage the vulnerability of AML cells to CDK6 to identify a combination therapy capable of targeting common biological processes shared by all leukemic cells, while sparing non-transformed cells. We demonstrate that the combined inhibition of CDK6 and LSD1 restores myeloid differentiation and depletes the leukemic progenitor compartment in AML samples. Mechanistically, this combination induces major changes in chromatin accessibility, leading to the transcription of differentiation genes and diminished LSC signatures. Remarkably, the combination is synergistic, induces durable changes in the cells, and is effective in PDX mouse models. While many AML samples exhibit only modest responses to LSD1 inhibition, co-targeting CDK6 restores the expected transcription response associated with LSD1 inhibition. Given the availability of clinical-grade CDK6 and LSD1 inhibitors, this combination holds significant potential for implementation in clinical settings through drug repositioning.

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Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML [RNAseq_MV4_11]

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Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML [RNAseq_MV4_11]

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Dual targeting of CDK6 and LSD1 is synergistic and overcomes differentiation blockade in AML

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LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade

Project description:Chromatin regulators play a broad role in regulating gene expression, and when gone awry, can lead to cancer. Here we demonstrate that ablation of the histone demethylase LSD1 in cancer cells increases repetitive element expression, including ERVs, and decreases expression of RNA-induced silencing complex (RISC) components. Significantly, this leads to dsRNA stress and activation of type 1 interferon, which stimulates anti-tumor T cell immunity and restrains tumor growth. Furthermore, LSD1 depletion enhances tumor immunogenicity and T cell infiltration in poorly immunogenic tumors, and elicits significant responses of checkpoint blockade-refractory mouse melanoma to anti-PD-1 therapy. Consistently, TCGA data analysis shows an inverse correlation between LSD1 expression and CD8+ T cell infiltration in various human cancers. Our study identifies LSD1 as a potent inhibitor of anti-tumor immunity and responsiveness to immunotherapy, and suggests LSD1 inhibition combined with PD-(L)1 blockade as a novel cancer treatment strategy.

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