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Review
. 2021 Jul;35(7):1873-1889.
doi: 10.1038/s41375-021-01218-0. Epub 2021 May 6.

Hypomethylating agents (HMA) for the treatment of acute myeloid leukemia and myelodysplastic syndromes: mechanisms of resistance and novel HMA-based therapies

Julia Stomper  1 , John Charles Rotondo  1   2 , Gabriele Greve  1   3 , Michael Lübbert  4   5
Affiliations
Review

Hypomethylating agents (HMA) for the treatment of acute myeloid leukemia and myelodysplastic syndromes: mechanisms of resistance and novel HMA-based therapies

Julia Stomper et al. Leukemia. 2021 Jul.

Abstract

Aberrant DNA methylation plays a pivotal role in tumor development and progression. DNA hypomethylating agents (HMA) constitute a class of drugs which are able to reverse DNA methylation, thereby triggering the re-programming of tumor cells. The first-generation HMA azacitidine and decitabine have now been in standard clinical use for some time, offering a valuable alternative to previous treatments in acute myeloid leukemia and myelodysplastic syndromes, so far particularly in older, medically non-fit patients. However, the longer we use these drugs, the more we are confronted with the (almost inevitable) development of resistance. This review provides insights into the mode of action of HMA, mechanisms of resistance to this treatment, and strategies to overcome HMA resistance including next-generation HMA and HMA-based combination therapies.

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Conflict of interest statement

ML has received research funding and travel support from Janssen-Cilag, study drugs from TEVA, Cheplapharm and Aristopharm, and compensation as a member of the scientific advisory board of Janssen-Cilag and Astex. All the other authors declare no potential competing interests.

Figures

Fig. 1
Fig. 1. Azanucleoside DNA-hypomethylating agents.
Chemical structures of cytidine (A), the cytidine analogs 5-azacytidine (B) and decitabine (C), and guadecitabine (SGI-110), a dinucleotide of decitabine and deoxyguanosine (D).
Fig. 2
Fig. 2. Schematic representation of azacitidine and decitabine uptake and metabolism.
5-aza-U 5-aza-uridine, 5-aza-dU 5-aza-2´-deoxyuridine, CDP cytidine diphosphate, CMP cytidine monophosphate, hCNT human concentrative nucleoside transporter, hENT human equilibrative nucleoside transporter, NDPK nucleoside diphosphate kinase, NMPK nucleoside monophosphate kinase, RNR ribonucleotide reductase.
Fig. 3
Fig. 3. Cell intrinsic factors associated with resistance to HMA therapy in myeloid malignancies.
CYC cytochrome c (release), ITGA5 integrin subunit alpha 5.
See this image and copyright information in PMC

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