The Class IIA Histone Deacetylase (HDAC) Inhibitor TMP269 Downregulates Ribosomal Proteins and Has Anti-Proliferative and Pro-Apoptotic Effects on AML Cells

SIMPLE SUMMARY: Epigenetic alterations strongly contribute to the development of various types of cancer, including blood cancers such as acute myeloid leukemia (AML). Unlike genetic mutations, epigenetic changes in cancer are reversible. Therefore, targeted modification of epigenetic regulators, such as histone deacetylases (HDACs), is under intense investigation. Here, we analyzed gene expression for all four classes of HDACs in AML patients compared to healthy controls. We observed significant overexpression of various HDACs, including the relatively unexplored HDAC class IIA members. To investigate the cellular consequences of HDAC inhibition, we treated AML cell lines with the class IIA HDAC inhibitor TMP269 and observed significant effects on the cellular proteome and the growth of AML cells. We further demonstrate that the combination of TMP269 and venetoclax results in enhanced cell apoptosis. Our work provides new data for the HDAC inhibitor TMP269 and suggests that TMP269 might be an alternative compound for polytherapy in AML. ABSTRACT: Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by altered myeloid progenitor cell proliferation and differentiation. As in many other cancers, epigenetic transcriptional repressors such as histone deacetylases (HDACs) are dysregulated in AML. Here, we investigated (1) HDAC gene expression in AML patients and in different AML cell lines and (2) the effect of treating AML cells with the specific class IIA HDAC inhibitor TMP269, by applying proteomic and comparative bioinformatic analyses. We also analyzed cell proliferation, apoptosis, and the cell-killing capacities of TMP269 in combination with venetoclax compared to azacitidine plus venetoclax, by flow cytometry. Our results demonstrate significantly overexpressed class I and class II HDAC genes in AML patients, a phenotype which is conserved in AML cell lines. In AML MOLM-13 cells, TMP269 treatment downregulated a set of ribosomal proteins which are overexpressed in AML patients at the transcriptional level. TMP269 showed anti-proliferative effects and induced additive apoptotic effects in combination with venetoclax. We conclude that TMP269 exerts anti-leukemic activity when combined with venetoclax and has potential as a therapeutic drug in AML.