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Emerging Epigenetic Therapeutics for Myeloid Leukemia: Modulating

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Emerging Epigenetic Therapeutics for Myeloid Leukemia: Modulating REVIEW ARTICLE Emerging epigenetic therapeutics for myeloid Ferrata Storti Foundation leukemia: modulating demethylase activity with ascorbate Andrew B. Das, Carlos C. Smith-Díaz and Margreet C.M. Vissers Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand Haematologica 2021 ABSTRACT Volume 106(1):14-25 he past decade has seen a proliferation of drugs that target epige - netic pathways. Many of these drugs were developed to treat Tacute myeloid leukemia, a condition in which dysregulation of the epigenetic landscape is well established. While these drugs have shown promise, critical issues persist. Specifically, patients with the same mutations respond quite differently to treatment. This is true even with highly specific drugs that are designed to target the underlying oncogenic driver mutations. Furthermore, patients who do respond may eventually develop resistance. There is now evidence that epigenetic heterogeneity contributes, in part, to these issues. Cancer cells also have a remarkable capacity to ‘rewire’ themselves at the epigenetic level in response to drug treatment, and thereby maintain expression of key oncogenes. This epigenetic plasticity is a promising new target for drug development. It is therefore important to consider combination therapy in cases in which both driver mutations and epigenetic plasticity are tar - geted. Using ascorbate as an example of an emerging epigenetic thera - peutic, we review the evidence for its potential use in both of these modes. We provide an overview of 2-oxoglutarate dependent dioxyge - nases with DNA, histone and RNA demethylase activity, focusing on those which require ascorbate as a cofactor. We also evaluate their role in the development and maintenance of acute myeloid leukemia. Using this information, we highlight situations in which the use of ascorbate Correspondence: to restore 2-oxoglutarate dependent dioxygenase activity could prove ANDREW B. DAS beneficial, in contrast to contexts in which targeted inhibition of specific [email protected] enzymes might be preferred. Finally, we discuss how these insights could be incorporated into the rational design of future clinical trials. Received: June 26, 2020. Accepted: September 17, 2020. Introduction Pre-published: October 22, 2020. Acute myeloid leukemia (AML) is a cancer that arises from the stem and progen - itor cells of the hematopoietic system. These abnormally differentiated, clonal cells https://doi.org/10.3324/haematol.2020.259283 infiltrate the bone marrow, blood and other tissues. Unless treatment is initiated early, the rapid onset of this proliferative disease is fatal. Over the past 50 years there have been remarkable improvements in the treatment of AML. Initially incur - ©2021 Ferrata Storti Foundation able, the 5-year survival for young patients (<60 years old) is now greater than Material published in Haematologica is covered by copyright. 50%. 1 This progress was initiated in the 1970s when the effectiveness of cytarabine All rights are reserved to the Ferrata Storti Foundation. Use of and anthracyclines was discovered. Subsequently, various regimens involving com - published material is allowed under the following terms and conditions: binations of the two drugs were studied to find the optimum dose, with bone mar - https://creativecommons.org/licenses/by-nc/4.0/legalcode. row transplants introduced as an option in 1977. Prognosis has been even better for Copies of published material are allowed for personal or inter - acute promyelocytic leukemia, a subset of AML in which the use of all- trans nal use. Sharing published material for non-commercial pur - retinoic acid (ATRA) and arsenic trioxide has increased 5-year survival to 90%. poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, However, for older patients, for whom intensive chemotherapy is not an option, 2 sect. 3. Reproducing and sharing published material for com - outcomes remain bleak with a median survival of 5-11 months. Clearly, more mercial purposes is not allowed without permission in writing effective treatments for AML are needed, with important clinical questions remain - from the publisher. ing, including why is there a variable response to drug therapy, and why do some patients develop resistance to therapy? When considering new treatments for AML, it is important to first evaluate our current understanding of the contributing 14 haematologica | 2021; 106(1) Emerging epigenetic therapeutics for AML Figure 1. Levels of heterogeneity in acute myeloid leukemia and potential treatment strategies to address them. See text for further details. variables. This will help to frame current and emerging mutational burden is low in AML compared to other can - treatment strategies for AML (Figure 1), and provide a cers, and that proteins involved in epigenetic processes are framework for considering ascorbate as an epigenetic ther - early drivers of the cancer phenotype. 6,10 This information apeutic. is of particular interest because the reversibility of epige - netic modifications makes these processes, and the pro - Genetic heterogeneity in acute myeloid leukemia teins that mediate them, attractive drug targets. 11-13 These As evidenced by the variable response to chemotherapy, data have also highlighted the potential for precision med - AML is a heterogeneous disease. As the technologies icine, where treatments can be matched to the patient on available to investigate AML have developed, our under - a case-by-case basis. In the past 5 years, selective standing of where this heterogeneity lies has expanded. inhibitors for mutations in FLT3 ,14 IDH1 15 and IDH2 16 have Morphological and cytogenetic heterogeneity have been gained approval from the Food and Drug Administration. studied for over 30 years and formed the basis for the There are also a growing number of clinical trials for drugs French-Amercian-British classification system. 3 As genetic targeting epigenetic writers (DOT1L, PRMT5), readers sequencing technologies improved, frequently mutated (BRD2/3/4) and erasers (HDAC, LSD1). 13 However, the genes were added to classification and prognostic predic - major difficulties with targeted therapy to date, epigenetic tion by the World Health Organization 4 and European or otherwise, are familiar adversaries: variable response to LeukemiaNet. 5 To date, next-generation sequencing tech - the drug, and drug resistance. At first glance this seems to nologies have shed the greatest light on heterogeneity in be a repetition of the same issues experienced with AML. In 2016, a landmark study that sequenced DNA chemotherapy. However, the nuance here is that patients samples from more than 1,540 AML patients found recur - with the same mutations respond quite differently to rent mutations in over 100 genes. 6 Combining this infor - treatment. This is reported even with highly specific drugs mation with cytogenetic and clinical data has shown that that are designed to target the common oncogenic driver AML comprises at least 11 different subgroups with prog - mutation. 15,17 By uncovering deeper layers of heterogeneity nostic relevance. 6,7 Therefore, substantial heterogeneity in in AML, this obstacle has provided an indication as to molecular pathology underpins the apparently homoge - how it may be overcome. nous phenotype of patients presenting in the clinic. Single- cell sequencing has added another layer of complexity to Epigenetic heterogeneity, plasticity and drug this scenario: multiple AML clones may exist in the same resistance patient with their relative proportions changing over time We have highlighted two reasons why patients respond with treatment and relapse, 8,9 with different co-occurring quite differently to treatment; inter-patient heterogeneity mutations contributing to different clinical outcomes. 6,7 (genetic) and intra-patient heterogeneity (genetic/clonal). A further insight emerging from large studies using However, these factors alone do not explain why some next-generation sequencing to investigate AML is that the patients eventually develop resistance to a targeted drug. haematologica | 2021; 106(1) 15 A.B. Das et al. The most commonly proffered reason is that the develop - OGDD utilize non-heme iron (Fe 2+ ), 2-oxoglutarate and ment of new mutations confers a survival advantage. 15,18 oxygen to catalyze a wide range of hydroxylation reac - This can be due the founding clone in the primary tumor tions. Many enzymes function as DNA, histone and RNA gaining mutations and evolving into the relapse clone, or demethylases and have been shown to require ascorbate a subclone of the founding clone surviving initial therapy, to maintain optimal activity (Table 1). This biochemistry gaining additional mutations and expanding at relapse. 19 underpins ascorbate’s link to epigenetics and has received However, there is growing evidence that non-genetic increasing attention in multiple contexts including can - resistance also plays a role. 20 Two key variables that con - cer. 32,33 The findings are particularly relevant for AML tribute towards this outcome are epigenetic heterogeneity because many of these demethylase enzymes are involved and epigenetic plasticity. in the development and maintenance of AML (Table 1). Of Epigenetic heterogeneity refers to the different epige - the 20 OGDD enzymes with demethylase activity listed netic states across a population of genetically identical in Table 1, 17 play a role in the development
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