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 

TITLE=The Combination of Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Delays KMT2A-Rearranged Leukemia Progression

JOURNAL=Frontiers in Oncology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.863329

DOI=10.3389/fonc.2022.863329

ISSN=2234-943X

ABSTRACT=<p>Rearrangements of the <italic>Mixed Lineage Leukemia</italic> (<italic>MLL/KMT2A</italic>) 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 <italic>via</italic> 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 (<italic>KMT2A:MLLT3</italic>) 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 <italic>KMT2A</italic> 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.</p>