Protein lysine acetylation in normal and leukaemic haematopoiesis: HDACs as possible therapeutic targets in adult AML

Abstract

Several new therapeutic strategies are now considered for acute myelogenous leukaemia (AML), including modulation of protein lysine acetylation through inhibition of histone deacetylases (HDACs): a large group of enzymes that alters the acetylation and, thereby, the function of a wide range of nuclear and cytoplasmic proteins. Firstly, HDACs can deacetylate histones as well as transcription factors, and can modulate gene expression through both these mechanisms. Secondly, acetylation is an important post-translational modulation of several proteins involved in the regulation of cell proliferation, differentiation and apoptosis (e.g., p53, tubulin, heat-shock protein 90). The only HDAC inhibitors that have been investigated in clinical studies of AML are butyrate derivatives, valproic acid and depsipeptide. In the first studies, the drugs have usually been used as continuous therapy for several weeks or months, and in most studies the drugs were used alone or in combination with all-trans retinoic acid for treatment of patients with relapsed or primary resistant AML. Neurological toxicity and gastrointestinal side effects seem to be common for all three drugs. Complete haematological remission lasting for several months has been reported for a few patients (< 5% of included patients), whereas increased peripheral blood platelet counts seem more common and have been described both for patients with AML and myelodysplastic syndromes. Taken together, these studies suggest that HDAC inhibition can mediate antileukaemic effects in AML, but for most patients the clinical benefit seems limited and further studies of combination therapy are required.

Acute myelogenous leukemia in a patient with Li–Fraumeni syndrome treated with valproic acid, theophyllamine and all-trans retinoic acid: a case report

“…The biological effects of HDAC inhibitors have been suggested to affect p53 through at least two different mechanisms: (i) altered histone acetylation with altered TP53 gene expression; and (ii) altered acetylation of the p53 protein. 10 In the present patient, we combined valproic acid with ATRA and theophyllamine. ATRA is used for differentiation induction in acute promyelocytic leukemia and can also induce biological alterations in other forms of AML.…”

“…10 HDACs deacetylate not only histones but also many other nuclear and cytoplasmic proteins including p53, heat shock protein 90, and several transcription factors and structural proteins. Thus, other mechanisms than altered histone acetylation may contribute to the effects of HDAC inhibitors on malignant cells, and p53-mediated effects may then be important.…”

Epigenetic regulation of normal and malignant hematopoiesis

“…The acetylation of specific lysine residues of transcription factors has been shown to affect the subcellular localization, DNA binding, transcriptional activity, protein-protein interactions and stability of several key transcription factors including p53, STAT3, RUNX1 and ETS, and not surprisingly, alterations in HAT/HDAC activity are linked to multiple cancers (Bruserud et al, 2006).…”

Functional characteristics and gene expression profiles of primary acute myeloid leukaemia cells identify patient subgroups that differ in susceptibility to histone deacetylase inhibitors

“…Therapeutic strategies targeting protein acetylation are now considered in many human malignancies, including AML (2). This can be achieved by inhibition of histone deacetylases (HDACs), a large group of enzymes that increase acetylation and thereby alters the function of a wide range of nuclear and cytoplasmic proteins (1,3,4) including histones, transcription factors (5) and several regulators of cell proliferation, differentiation and apoptosis (2,6,7).…”