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

• Published in: International journal of molecular sciences 2018-10, Vol.19 (10), p.3091
• Main Author: Ungerstedt, Johanna S
• Format: Article
• Language: English
• Subjects: acute myeloid leukemia; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cancer och onkologi; Cell- och molekylärbiologi; chronic myelomonocytic leukemia; DNA Methylation; Drug Evaluation, Preclinical; Epigenesis, Genetic - drug effects; Gene Expression Regulation, Leukemic - drug effects; Hematopoiesis - drug effects; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Histones - metabolism; Humans; Klinisk medicin; Leukemia, Myeloid - drug therapy; Leukemia, Myeloid - genetics; Leukemia, Myeloid - metabolism; Leukemia, Myeloid - pathology; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Mutation; myelodysplastic syndromes; myeloid mutations; Myeloproliferative Disorders - drug therapy; Myeloproliferative Disorders - genetics; Myeloproliferative Disorders - metabolism; Myeloproliferative Disorders - pathology; Review; systemic mastocytosis; treatment; Treatment Outcome
• ISSN: 1422-0067; 1422-0067
• DOI: 10.3390/ijms19103091

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.