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Single-cell multi-omics analyses reveal EZH2 as a main driver of retinoic acid resistance in PLZF-RARA leukemia

Authors
  • Poplineau, M.
  • Platet, N.
  • Mazuel, A.
  • Hérault, L.
  • Koide, S.
  • Kuribayashi, W.
  • Carbuccia, N.
  • N’Guyen, L.
  • Vernerey, J.
  • Oshima, M.
  • Birnbaum, D.
  • Iwama, A.
  • Duprez, Estelle
Publication Date
Mar 29, 2022
Identifiers
DOI: 10.1101/2022.01.04.474890
OAI: oai:HAL:hal-03622501v1
Source
HAL
Keywords
Language
English
License
Unknown
External links

Abstract

Cancer relapse is caused by a subset of malignant cells that are resistant to treatment. To characterize resistant cells and their vulnerabilities, we studied the retinoic acid (RA)-resistant PLZF-RARA acute promyelocytic leukemia (APL) using single-cell multi-omics. We uncovered transcriptional and chromatin heterogeneity in leukemia cells and identified a subset of cells resistant to RA that depend on a fine-tuned transcriptional network targeting the epigenetic regulator Enhancer of Zeste Homolog 2 (EZH2). Epigenomic and functional analyses validated EZH2 selective dependency of PLZF-RARA leukemia and its driver role 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.

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