Type: Oral
Session: 602. Myeloid Oncogenesis: Basic: Cellular Mechanisms and Therapeutic Strategies
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Acute Myeloid Malignancies, AML, Translational Research, Diseases, Treatment Considerations, Myeloid Malignancies
In the present work, we questioned whether EZH2 non-canonical activity may contribute more generally to resistance in non-APL AML. To do so, we questioned non-APL public AML transcriptomic datasets (BeatAML and TCGA). At first, we classified non-APL AML patients with high and low EZH2 expression and revealed that patients with high EZH2 expression were enriched in metabolic signatures reflecting chemotherapy resistance (i-e HighOXPHOS). Next, we computed a new EZH2-related signature (i-e; 61 common genes to BeatAML and TGCA obtained by retaining the 200 most differentially expressed genes in patients with high and low EZH2 expression) and found that this signature was positively correlated with AraC low responder patients. Besides, we showed that our computed non-canonical and non-methyltransferase EZH2 and ReP signatures were associated (i) with HighOXPHOS and leukemic stem cells maintenance signatures in AML patients and (ii) relapse of patients following AraC treatment.
Next, we investigated the relevance of targeting EZH2 in AML using an EZH2 PROTAC synthetized in our laboratory and derived from the previously published MS177 EZH2 degrader (Wang, Nat. Cell Biol., 2022). Using several leukemic cell lines, we showed that chemo-resistant cell lines, more especially AraC resistant cells, were highly sensitive to EZH2 degradation (fifty times more sensitive than AraC sensitive cells) but were not sensitive to the catalytic EZH2 inhibitor Tazemetostat. We then studied the potential synergistic effect between the EZH2 degrader and AraC and did not observe any additional beneficial effect with the combo therapy. However, we showed that EZH2 degradation has strong synergistic effect with RA in killing AML cells in vitro, suggesting that EZH2 degradation may sensitize chemotherapy resistant cells to RA.
Finally, by coupling omics approaches on AML cell line resistant to AraC, we are currently investigating mechanisms that dictate EZH2 activities (canonical/non-canonical) and characterizing these activities at the functional level. Proteomics screening revealed specific PTMs on EZH2 and variation in its interacting partners that may contribute to AraC resistance in AML.
Altogether, these data reinforce (i) the intimate link between EZH2 non-canonical activity and AraC resistance in non-APL AML and (ii) support the need to preclinically investigate the therapeutic value of targeting non-canonical EZH2 activities not only to sensitize non-APL AML to RA but also to overcome chemotherapy resistance in non-APL AML.
Disclosures: No relevant conflicts of interest to declare.
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