Abstract
Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors. Although clinical advances in AML have been made, especially in young patients, long-term disease-free survival remains poor, making this disease an unmet therapeutic challenge. Epigenetic alterations and mutations in epigenetic regulators contribute to the pathogenesis of AML, supporting the rationale for the use of epigenetic drugs in patients with AML. While hypomethylating agents have already been approved in AML, the use of other epigenetic inhibitors, such as histone deacetylases (HDAC) inhibitors (HDACi), is under clinical development. HDACi such as Panobinostat, Vorinostat, and Tricostatin A have been shown to promote cell death, autophagy, apoptosis, or growth arrest in preclinical AML models, yet these inhibitors do not seem to be effective as monotherapies, but rather in combination with other drugs. In this review, we discuss the rationale for the use of different HDACi in patients with AML, the results of preclinical studies, and the results obtained in clinical trials. Although so far the results with HDACi in clinical trials in AML have been modest, there are some encouraging data from treatment with the HDACi Pracinostat in combination with DNA demethylating agents.
Highlights
Acute myeloid leukemia (AML) is a heterogeneous clonal disorder characterized by the uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors in peripheral blood and bone marrow [1,2,3,4,5,6]
It is well reported that global histoneacetylation levels are aberrantly altered in cancer, but HDACs are much more than histone deacetylases
Epigenetic therapy is still poorly developed in AML, but it is a very promising field that is rapidly evolving
Summary
Acute myeloid leukemia (AML) is a heterogeneous clonal disorder characterized by the uncontrolled proliferation, differentiation arrest, and accumulation of immature myeloid progenitors in peripheral blood and bone marrow [1,2,3,4,5,6]. Cancers 2019, 11, 1794 disease-free survival and overall survival have improved in recent years, improvement has been mostly observed in younger patients. Approximately 40% of patients younger than 60 years of age may obtain long-term disease-free survival with current therapy. Most of these enzymes have been shown to be deregulated or mutated in several cancers and in AML [15,16,17,18] This fact, together with the evidence that epigenetic modifications are pharmacologically reversible, has placed epigenetic drugs at the center of both clinical and preclinical research in AML. Since the role of DNA methylation and the effect of hypomethylating agents in AML has been recently reviewed [19,20], we will focus on the rationale for the use of HDAC inhibitors (HDACi) for AML treatment. We will discuss the novel evidence regarding the synergistic effects, in preclinical and clinical studies in AML, of HDACi with DNA hypomethylating agents and other inhibitors
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