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Integrative single-cell multi-omics analyses to understand Leukemia resistance.

Lecture by Dr Mathilde Poplineau, CRCM, Marseille
Teams videoconference given on Friday 27 September as part of the CRCT’s Scientific Animation Committee

Cancer cell heterogeneity is a major driver of therapy resistance. To characterize resistant cells and their vulnerabilities, we studied the PLZF-RARA variant of acute promyelocytic leukemia (APL), resistant to retinoic acid (RA), using single-cell multi-omics. We uncovered transcriptional and chromatin heterogeneity in leukemia cells. We identified a subset of cells resistant to RA with proliferation, DNA replication and repair signatures, that depend on a fine-tuned E2F transcriptional network targeting the epigenetic regulator Enhancer of Zeste Homolog 2 (EZH2). Epigenomic and functional analyses validated the driver role of EZH2 in RA resistance. Targeting pan-EZH2 activities (canonical/non-canonical) was necessary to eliminate leukemia relapse initiating cells, which underlies a dependency of resistant cells on an EZH2 non-canonical activity and the necessity to degrade EZH2 to overcome resistance.
Our study provides critical insights into the mechanisms of RA resistance that allow us to eliminate treatment-resistant leukemia cells by targeting EZH2, thus highlighting a potential targeted therapy approach (Poplineau et al, Blood, 2022). Beyond RA resistance and APL context, our study also demonstrates the power of single-cell multi-omics to identify, characterize and clear therapy-resistant cells.

Videoconference