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AML: Deacetylases

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Book cover Targeted Therapy of Acute Myeloid Leukemia

Part of the book series: Current Cancer Research ((CUCR))

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Abstract

Human malignancies, including acute myeloid leukemia (AML), are driven by genetic lesions that result in loss of function of tumor suppressor genes and/or activation of oncogenes. In addition to changes in the genome, we now understand that aberrations to the epigenome, either through mutation of genes encoding epigenetic regulators, or inappropriate recruitment of epigenetic enzymes to genetic loci by oncogenic fusion proteins commonly found in AML, can lead to neoplastic transformation. Alterations in the function, expression, or localization of histone acetyltransferases (HATS) and histone deacetylases (HDACs) have been shown to be important for the development of AML. Compounds that target these epigenetic regulators have now been developed and therefore offer a new therapeutic option for patients with AML driven by alterations to the epigenome.

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Authors and Affiliations

  1. Cancer Therapeutics Program, Peter MacCallum Cancer Centre, St. Andrews Place, 3002, East Melbourne, Victoria, Australia

    Margherita Ghisi & Ricky W. Johnstone

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  1. Margherita Ghisi
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  1. Dept. Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Michael Andreeff

Conclusions

Conclusions

A growing amount of data indicates that alterations in the activity or expression of histone-modifying enzymes play a critical role in the development and progression of AML, and, thus, could constitute particularly promising therapeutic targets for these diseases. In the recent years, there has been a strong focus on the development and use of epigenetic drugs and in particular of HDACi for the treatment of hematologic malignancies, including AML and MDS. Many compounds have been tested in preclinical setting giving encouraging results, and some have proceeded to evaluation in phase I/II clinical trials on AML patients. Although some promising results have been obtained with HDACi (especially in combination studies) in patients with AML, so far, the therapeutic success of these drugs has been limited by a series of different factors. First of all, some histone-modifying enzymes seem to play very different and specific roles in distinct classes of AML, depending on the cellular origin and the genetic background of the leukemic cells. Thus, inhibitors of specific enzymes or classes of enzymes are likely to have very different effects on different subtypes of leukemias. Another important issue is that in many cases the exact mechanism by which these epigenetic drugs exert their therapeutic activity is still not clear, and this obviously complicates the optimization of their clinical use.

A better understanding of the cancer-specific dependency on different epigenetic regulators , the development of more selective inhibitors of epigenetic enzymes, and a better stratification of patients enrolled in the clinical studies will probably greatly improve in the future the performance and the impact of epigenetic drugs in the clinics.

Acknowledgments

RWJ is a principal research fellow of the National Health and Medical Research Council of Australia (NHMRC) and supported by NHMRC Program and Project Grants, the Susan G Komen Breast Cancer Foundation, Cancer Council Victoria, The Victorian Cancer Agency, The Leukemia Foundation of Australia and the Victorian Breast Cancer Research Consortium. MG is a postdoctoral fellow supported by the Italian Cancer Research Foundation (FIRC).

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Ghisi, M., Johnstone, R. (2015). AML: Deacetylases. In: Andreeff, M. (eds) Targeted Therapy of Acute Myeloid Leukemia. Current Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1393-0_21

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