Author:
Xiao Lin,Karsa Mawar,Ronca Emma,Bongers Angelika,Kosciolek Angelika,El-Ayoubi Ali,Revalde Jezrael L.,Seneviratne Janith A.,Cheung Belamy B.,Cheung Laurence C.,Kotecha Rishi S.,Newbold Andrea,Bjelosevic Stefan,Arndt Greg M.,Lock Richard B.,Johnstone Ricky W.,Gudkov Andrei V.,Gurova Katerina V.,Haber Michelle,Norris Murray D.,Henderson Michelle J.,Somers Klaartje
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.
Funder
Cancer Institute NSW
Cancer Australia
National Health and Medical Research Council
Cancer Council NSW
Cancer Council Victoria
Tour de Cure
Anthony Rothe Memorial Trust
Cited by
10 articles.
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