Epigenetic regulation of protein translation in KMT2A-rearranged AML.

Autor: Lenard A; Division of Pediatric Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA., Xie HM; Division of Pediatric Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA., Pastuer T; Division of Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children's Hospital Colorado Aurora, CO., Shank T; Division of Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children's Hospital Colorado Aurora, CO., Libbrecht C; Division of Pediatric Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA., Kingsley M; Division of Pediatric Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA., Riedel SS; Division of Pediatric Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA., Yuan ZF; Division of Pediatric Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA., Zhu N; Stem Cell Biology and Hematopoiesis Program, Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI; Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI., Neff T; Division of Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children's Hospital Colorado Aurora, CO., Bernt KM; Division of Pediatric Oncology, Department of Pediatrics, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Abramson Cancer Center, Philadelphia, PA. Electronic address: berntk@email.chop.edu.
Jazyk: angličtina
Zdroj: Experimental hematology [Exp Hematol] 2020 May; Vol. 85, pp. 57-69. Date of Electronic Publication: 2020 May 11.
DOI: 10.1016/j.exphem.2020.04.007
Abstrakt: Inhibition of the H3K79 histone methyltransferase DOT1L has exhibited encouraging preclinical and early clinical activity in KMT2A (MLL)-rearranged leukemia, supporting the development of combinatorial therapies. Here, we investigated two novel combinations: dual inhibition of the histone methyltransferases DOT1L and EZH2, and the combination with a protein synthesis inhibitor. EZH2 is the catalytic subunit in the polycomb repressive complex 2 (PRC2), and inhibition of EZH2 has been reported to have preclinical activity in KMT2A-r leukemia. When combined with DOT1L inhibition, however, we observed both synergistic and antagonistic effects. Interestingly, antagonistic effects were not due to PRC2-mediated de-repression of HOXA9. HOXA cluster genes are key canonical targets of both KMT2A and the PRC2 complex. The independence of the HOXA cluster from PRC2 repression in KMT2A-r leukemia thus affords important insights into leukemia biology. Further studies revealed that EZH2 inhibition counteracted the effect of DOT1L inhibition on ribosomal gene expression. We thus identified a previously unrecognized role of DOT1L in regulating protein production. Decreased translation was one of the earliest effects measurable after DOT1L inhibition and specific to KMT2A-rearranged cell lines. H3K79me2 chromatin immunoprecipitation sequencing patterns over ribosomal genes were similar to those of the canonical KMT2A-fusion target genes in primary AML patient samples. The effects of DOT1L inhibition on ribosomal gene expression prompted us to evaluate the combination of EPZ5676 with a protein translation inhibitor. EPZ5676 was synergistic with the protein translation inhibitor homoharringtonine (omacetaxine), supporting further preclinical/clinical development of this combination. In summary, we discovered a novel epigenetic regulation of a metabolic process-protein synthesis-that plays a role in leukemogenesis and affords a combinatorial therapeutic opportunity.
(Copyright © 2020 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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