PRC2-mediated apoptosis evasion is a therapeutic target of MDS/AML harboring inv(3)/t(3;3) and monosomy 7 Journal Article
| Authors: | Kunimoto, H.; Miura, A.; Sagisaka, M.; Ito, M.; Maenosono, R.; Yamauchi, H.; Nishimura, K.; Honma, D.; Tsutsumi, S.; Adachi, A.; Sakuma, T.; Ohashi, T.; Teranaka, H.; Ikeda, J.; Samukawa, S.; Toya, T.; Harada, Y.; Doki, N.; Cai, S. F.; Maki, H.; Goto, H.; Yoshimi, A.; Nakajima, H. |
| Article Title: | PRC2-mediated apoptosis evasion is a therapeutic target of MDS/AML harboring inv(3)/t(3;3) and monosomy 7 |
| Abstract: | Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) harboring both inv(3)/t(3;3) and monosomy 7 (−7) are highly aggressive myeloid cancers of which molecular pathogenesis and therapeutic vulnerability remain elusive. High throughput drug screens, CUT&Tag/RNA sequence, and functional assays using human MDS/AML cells revealed that EZH2 inhibitors efficiently induce apoptosis preferentially in MDS/AML with inv(3)/t(3;3) and −7 through the activation of GADD45γ-p38-p53 axis. EVI1 activated in 3q-rearranged MDS/AML was responsible for GADD45γ silencing by direct binding to its consensus sequence within GADD45γ promoter and recruitment of PRC2 complex via interaction with EZH2, which can be therapeutically targeted by EZH2 inhibition. MDS/AML with inv(3)/t(3;3) and −7 showed preferential sensitivity to EZH2 inhibition in both mouse model and patient samples. Thus, MDS/AML cells with inv(3)/t(3;3) and −7 possess apoptosis evasion mechanism through EVI1-PRC2-mediated repression of GADD45γ-p38-p53 axis, which is a potential therapeutic vulnerability in MDS/AML patients with these high-risk cytogenetic lesions. © 2025 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association. |
| Keywords: | controlled study; protein expression; human cell; promoter region; nonhuman; drug targeting; gemcitabine; antineoplastic agent; mouse; apoptosis; mitogen activated protein kinase inhibitor; animal experiment; animal model; cytogenetics; vincristine; high throughput screening; in vitro study; drug effect; docetaxel; chromosome aberration; myelodysplastic syndrome; leukemia cell; rna sequence; chromosome 7; transcription factor ezh2; consensus sequence; acute myeloid leukemia; trametinib; growth arrest and dna damage inducible protein 45; monosomy 7; human; article; tazemetostat; valemetostat; cut tag sequencing |
| Journal Title: | HemaSphere |
| Volume: | 9 |
| Issue: | 7 |
| ISSN: | 2572-9241 |
| Publisher: | Lippincott Williams & Wilkins |
| Date Published: | 2025-07-01 |
| Start Page: | e70149 |
| Language: | English |
| DOI: | 10.1002/hem3.70149 |
| PROVIDER: | scopus |
| PMCID: | PMC12255905 |
| PUBMED: | 40657304 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
