Epigenetic regulators as promising therapeutic targets in acute myeloid leukemia
Therapeutic Advances in Haematology
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Gallipoli, P., Giotopoulos, G., & Huntly, B. (2015). Epigenetic regulators as promising therapeutic targets in acute myeloid leukemia. Therapeutic Advances in Haematology, 6 103-119. https://doi.org/10.1177/2040620715577614
Acute myeloid leukemia (AML), the most prevalent acute leukemia in adults, is an aggressive hematological malignancy arising in hematopoietic stem and progenitor cells. With the exception of a few specific AML subtypes, the mainstays of treatment have not significantly changed over the last 20 years, and are still based on standard cytotoxic chemotherapy. As a result, clinical outcome remains poor for the majority of patients, with overall long-term survival in the region of 20–30%. Recent successes in characterizing the genetic landscape of AML have highlighted that, despite its heterogeneity, many cases of AML carry recurrent mutations in genes encoding epigenetic regulators. Transcriptional dysregulation and altered epigenetic function have therefore emerged as exciting areas in AML research and it is becoming increasingly clear that epigenetic dysfunction is central to leukemogenesis in AML. This has subsequently paved the way for the development of epigenetically targeted therapies. In this review, we will discuss the most recent advances in our understanding of the role of epigenetic dysregulation in AML pathobiology. We will particularly focus on those altered epigenetic programs that have been shown to be central to the development and maintenance of AML in preclinical models. We will discuss the recent development of therapeutics specifically targeting these key epigenetic programs in AML, describe their mechanism of action and present their current clinical development. Finally, we will discuss the opportunities presented by epigenetically targeted therapy in AML and will highlight future challenges ahead for the AML community, to ensure that these novel therapeutics are optimally translated into clinical practice and result in clinical improvement for AML patients.
acute myeloid leukemia, epigenetics, targeted therapy
We would like to thank all the members of the Huntly laboratory and our funders Leukaemia Lymphoma Research, Kay Kendall Leukaemia fund, the Medical Research Council UK, the Wellcome Trust, the Cambridge NIHR Biomedical Research Centre, Leukemia & Lymphoma Society US, the Academy of Medical Sciences UK and Lady Tata Memorial Trust. We apologise to writers whose work we have failed to cite due to space constraints.
Medical Research Council (MR/M010392/1)
Worldwide Cancer Research (14-1069)
External DOI: https://doi.org/10.1177/2040620715577614
This record's URL: https://www.repository.cam.ac.uk/handle/1810/247743