The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression
- Author(s)
- Xiao, L; Karsa, M; Ronca, E; Bongers, A; Kosciolek, A; El-Ayoubi, A; Revalde, JL; Seneviratne, JA; Cheung, BB; Cheung, LC; Kotecha, RS; Newbold, A; Bjelosevic, S; Arndt, GM; Lock, RB; Johnstone, RW; Gudkov, AV; Gurova, KV; Haber, M; Norris, MD; Henderson, MJ; Somers, K;
- Journal Title
- Frontiers in Oncology
- Publication Type
- Research article
- Abstract
- Rearrangements of the Mixed Lineage Leukemia (MLL/KMT2A) gene are present in approximately 10% of acute leukemias and characteristically define disease with poor outcome. Driven by the unmet need to develop better therapies for KMT2A-rearranged leukemia, we previously discovered that the novel anti-cancer agent, curaxin CBL0137, induces decondensation of chromatin in cancer cells, delays leukemia progression and potentiates standard of care chemotherapies in preclinical KMT2A-rearranged leukemia models. Based on the promising potential of histone deacetylase (HDAC) inhibitors as targeted anti-cancer agents for KMT2A-rearranged leukemia and the fact that HDAC inhibitors also decondense chromatin via an alternate mechanism, we investigated whether CBL0137 could potentiate the efficacy of the HDAC inhibitor panobinostat in KMT2A-rearranged leukemia models. The combination of CBL0137 and panobinostat rapidly killed KMT2A-rearranged leukemia cells by apoptosis and significantly delayed leukemia progression and extended survival in an aggressive model of MLL-AF9 (KMT2A:MLLT3) driven murine acute myeloid leukemia. The drug combination also exerted a strong anti-leukemia response in a rapidly progressing xenograft model derived from an infant with KMT2A-rearranged acute lymphoblastic leukemia, significantly extending survival compared to either monotherapy. The therapeutic enhancement between CBL0137 and panobinostat in KMT2A-r leukemia cells does not appear to be mediated through cooperative effects of the drugs on KMT2A rearrangement-associated histone modifications. Our data has identified the CBL0137/panobinostat combination as a potential novel targeted therapeutic approach to improve outcome for KMT2A-rearranged leukemia.
- Keywords
- KMT2A-rearranged leukemia; chromatin; curaxin CBL0137; histone deacetylase inhibition; infant leukemia
- Department(s)
- Laboratory Research
- PubMed ID
- 35677155
- Publisher's Version
- https://doi.org/10.3389/fonc.2022.863329
- Open Access at Publisher's Site
https://doi.org/10.3389/fonc.2022.863329- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-05-16 01:15:07
Last Modified: 2025-05-16 01:16:07