3115 – INTEGRATIVE MULTI-OMICS ANALYSIS FOR UNDERSTANDING ACUTE PROMYELOCYTIC LEUKEMIA RESISTANCE: EZH2 ON THE ROAD

• Published in: Experimental hematology Vol. 100; p. S98
• Main Authors: Poplineau, Mathilde, Hérault, Léonard, Mazuel, Adrien, Platet, Nadine, Koide, Shuhei, Kuribayashi, Wakako, Carbuccia, Nadine, N'Guyen, Lia, Vernerey, Julien, Oshima, Motohiko, Birnbaum, Daniel, Lachaud, Christophe, Iwama, Atsushi, Duprez, Estelle
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.08.2021
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2021.12.332

Oncogenic chimeric proteins play important role in the initiation and development of Acute Myeloid Leukemia (AML) and influence the response to therapeutics. Acute Promyelocytic Leukemia (APL), the M3 subtype of AML, is a good model to illustrate these problematics. Indeed, APL driven by PML/RARA t(15;17) or PLZF/RARA t(11;17) behave differently to differentiation therapeutics. Both APLs differentiate in vivo upon Retinoic Acid (RA) exposure; however, while PML/RARA APL patients exhibit partial or complete remission, PLZF/RARA APL patients remain clinically resistant. In the present study we aim to decipher transcriptional and epigenetic networks that is linked to t(11;17) APL resistance towards RA. We first developed an integrative single-cell multi-omics analysis (scRNAseq and scATACseq) to identify and characterize relapse-initiating cells (RICs) in PLZF/RARA expressing cells. We revealed substantial transcriptional heterogeneity and differentiation states within the APL cell population. We also uncovered a subpopulation with a strong DNA repair signature ("Rep" cluster) which is characteristic of RICs and may cause RA resistance. This putative PLZF/RARA RICs were characterized by a transcriptional network involving E2f1 or Tfdp1 transcription factors targeting the histone methyltransferase Ezh2. To test the hypothesis that Ezh2 is involved in RA resistance we combined epigenomic profiling (ChIPseq analyses) with mouse-derived models for Ezh2 catalytic inhibition (GSK126) and for total Ezh2 KO (Ezh2fl/fl model). We revealed that Ezh2 canonical activity was involved in RA response while its non-canonical activity, linked to DNA repair mechanisms, was required for RA resistance. Altogether these data uncover a dual role of Ezh2 in APL and suggest that targeting non-canonical Ezh2 activity could be a new promising therapeutic approach for RA resistant APL.