Epigenetic Modifiers in Myeloid Malignancies: The Role of Histone Deacetylase Inhibitors

Abstract

Myeloid hematological malignancies are clonal bone marrow neoplasms, comprising of acute myeloid leukemia (AML), the myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), the myeloproliferative neoplasms (MPN) and systemic mastocytosis (SM). The field of epigenetic regulation of normal and malignant hematopoiesis is rapidly growing. In recent years, heterozygous somatic mutations in genes encoding epigenetic regulators have been found in all subtypes of myeloid malignancies, supporting the rationale for treatment with epigenetic modifiers. Histone deacetylase inhibitors (HDACi) are epigenetic modifiers that, in vitro, have been shown to induce growth arrest, apoptotic or autophagic cell death, and terminal differentiation of myeloid tumor cells. These effects were observed both at the bulk tumor level and in the most immature CD34⁺38^- cell compartments containing the leukemic stem cells. Thus, there is a strong rationale supporting HDACi therapy in myeloid malignancies. However, despite initial promising results in phase I trials, HDACi in monotherapy as well as in combination with other drugs, have failed to improve responses or survival. This review provides an overview of the rationale for HDACi in myeloid malignancies, clinical results and speculations on why clinical trials have thus far not met the expectations, and how this may be improved in the future.

Keywords: acute myeloid leukemia; chronic myelomonocytic leukemia; myelodysplastic syndromes; myeloid mutations; systemic mastocytosis; treatment.

Figure 1

DNA methylation and demethylation. DNMT3A is commonly mutated in acute myeloid leukemia (AML), IDH1, 2 mutations are found in AML, and TET2 is frequently mutated in all myeloid malignancies. Azacitidine and decitabine are DNA demethylating agents, inhibiting DNA methyl transferases (DNMTs).

Figure 2

Histone modifications on the N terminal tail of histone H3 and H4. For simplicity, only methylation, acetylation and phosphorylation are depicted, however modifications also include arginine methylation and ubiquitination marks.

Figure 3

Epigenetic writers are histone acetyl transferases HAT (KAT), histone lysine methyl transferase (KMT) and PRMTs (protein arginine methyl transferases), readers are bromodomain proteins like BET family proteins, and erasers are histone deacetylase inhibitors (HDACi), KDM (lysine/histone demethylases) and phosphatases. Inhibitors or writers, readers and erasers are being developed and are in clinical trials for myeloid malignancies, for example HDACi, bromodomain BET inhibitor Q1 and DOT1L inhibitors, of which the latter are in clinical phase I trials.

Figure 4

Factors associated with histone or non-histone protein lysine acetylation/methylation, affected in hematological malignancies. In brackets are listed non-histone targets of HAT (KAT) and histone deacetylases (HDACs). See text for details on how these epigenetic factors are associated with myeloid malignancies.