Emerging therapeutic targets in human acute myeloid leukemia (part 2) – bromodomain inhibition should be considered as a possible strategy for various patient subsets

Abstract

The recent advances in our understanding of leukemogenesis have clearly demonstrated that human acute myeloid leukemia is a heterogeneous malignancy, and several disease mechanisms should probably be regarded as possible therapeutic targets only for specific subsets of patients and not for acute myeloid leukemia in general. One promising strategy for epigenetic targeting is inhibition of the binding between bromodomain-containing transcription regulators and acetylated lysine residues on histones. This possible approach has been investigated especially for patients with 11q23 and chromosome 8 abnormalities. An alternative target is the histone methyltransferase COT1L. Major challenges for both approaches will be to clarify how these strategies should be combined with each other or with conventional chemotherapy, and whether their use should be limited to certain subsets of patients.

Keywords:

• acetylation
• acute myeloid leukemia
• bromodomain
• epigenetic
• histone
• methyl transferase
• methylation
• therapy

Financial & competing interests disclosure

H Reikvam and T van Hoang’s research was supported by the Helse-Vest and the Norwegian Cancer Society. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Acute myeloid leukemia (AML) is a very heterogeneous disease with regard to genetic abnormalities and the molecular mechanisms involved in leukemogenesis, the most effective therapeutic targeting of molecular mechanisms that are driving the leukemogenesis will probably differ between patients.

• Bromodomain inhibition (i.e., inhibition of transcriptional regulators recognizing acetylated residues on histones) is an emerging strategy, especially for patients with (certain) 11q23 abnormalities, certain chromosome 8 abnormalities and possibly also NPM1 and isocitrate dehydrogenase mutations.

• Inhibition of the methyltransferase DOC1L may be an alternative epigenetic strategy in AML with 11q23 abnormalities.

• The major future challenges are to clarify whether these targeted therapies should be used as single drug treatment or in combinations, and whether they should be used only for certain subsets of patients.