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Primary acute myeloid leukemia cells with IDH1 or IDH2 mutations respond to a DOT1L inhibitor in vitro

Leukemia volume 28, pages 2403–2406 (2014)Cite this article

Epigenetic dysregulation represents an emerging paradigm in the pathogenesis of myeloid malignancies, and the pharmacologic targeting of pathways involved in regulating epigenetic modifications is a promising therapeutic strategy.1 Potential targets include recurrently mutated genes encoding epigenetic modifiers (for example, DNMT3A, IDH1/2, TET2, EZH2), and altered epigenetic modifiers (like mixed lineage leukemia (MLL) fusion genes) that are known to initiate acute myeloid leukemia (AML).2 Some leukemias with MLL translocations are dependent on the activity of DOT1L, a histone methyltransferase responsible for trimethylation of histone 3 on lysine 79 (H3K79); small-molecule inhibitors of DOT1L, like EPZ004777, can disrupt leukemic progression.3, 4, 5 DOT1L inhibitors are in various stages of clinical development for MLL-rearranged leukemias, but it is currently unclear whether these inhibitors may also be active in AML cases that lack MLL rearrangements.

We recently developed an in vitro culture system for primary AML cells that captures the genetic complexity of primary AML samples, and that can be used to test the impact of novel pharmacologic agents on AML cells.6 In vitro testing of primary leukemic samples has been very challenging for DOT1L inhibitors, which requires exposure to cells for more than 1 week. However, with our system, primary human AML cells can be expanded for up to 2 weeks. We used this approach to test the effects of DOT1L inhibition against a set of cryopreserved, genomically characterized de novo AML patient samples, collected through a study approved by the Human Research Protection Office at Washington University School of Medicine after patients provided informed consent.

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Acknowledgements

Technical assistance was provided by the Alvin J. Siteman Cancer Center Tissue Procurement Core, the High Speed Cell Sorter Core, and the Molecular and Genomic Analysis Core at Washington University School of Medicine and Barnes-Jewish Hospital in St Louis, MO, which are all supported by the National Cancer Institute Cancer Center Support Grant P30CA91842. This work was supported by National Institutes of Health grant R01CA162086 (TJL), PO1CA101937 (TJL), K08HL116605 (JMK) and the Barnes Jewish Hospital Foundation (TJL), as well as the Doris Duke Charitable Foundation to Washington University (SMS, Clinical Research Fellow).

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  1. Division of Oncology, Department of Internal Medicine, Section of Stem Cell Biology, Washington University in St Louis School of Medicine, St Louis, MO, USA

    S M Sarkaria, M J Christopher & T J Ley

  2. Department of Pathology and Immunology, Washington University in St Louis School of Medicine, St Louis, MO, USA

    J M Klco

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  1. S M Sarkaria
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Correspondence to T J Ley.

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Sarkaria, S., Christopher, M., Klco, J. et al. Primary acute myeloid leukemia cells with IDH1 or IDH2 mutations respond to a DOT1L inhibitor in vitro. Leukemia 28, 2403–2406 (2014). https://doi.org/10.1038/leu.2014.235

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