Mechanisms of Action of Hypomethylating Agents: Endogenous Retroelements at the Epicenter
Abnormal DNA methylation patterns are thought to drive the pathobiology of high-risk myelodysplastic syndromes (HR-MDS) and acute myeloid leukemia (AML). Sixteen years after their initial approval, the hypomethylating agents (HMAs), 5-azacytidine (AZA) and 5-aza-2′-deoxycytidine, remain the mainstay...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.650473/full |
| _version_ | 1819117188776198144 |
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| author | Chryssoula Kordella Eleftheria Lamprianidou Ioannis Kotsianidis |
| author_facet | Chryssoula Kordella Eleftheria Lamprianidou Ioannis Kotsianidis |
| author_sort | Chryssoula Kordella |
| collection | DOAJ |
| description | Abnormal DNA methylation patterns are thought to drive the pathobiology of high-risk myelodysplastic syndromes (HR-MDS) and acute myeloid leukemia (AML). Sixteen years after their initial approval, the hypomethylating agents (HMAs), 5-azacytidine (AZA) and 5-aza-2′-deoxycytidine, remain the mainstay of treatment for HR-MDS and AML. However, a connection of the hypomethylating or additional effects of HMAs with clinical responses remains yet to be shown, and the mode of action of HMAs remains obscure. Given the relatively short-lived responses and the inevitable development of resistance in HMAs, a thorough understanding of the antineoplastic mechanisms employed by HMAs holds critical importance. Recent data in cancer cell lines demonstrate that reactivation of endogenous retroelements (EREs) and induction of a cell-intrinsic antiviral response triggered by RNA neotranscripts may underlie the antitumor activity of HMAs. However, data on primary CD34+ cells derived from patients with HR-MDS failed to confirm a link between HMA-mediated ERE modulation and clinical response. Though difficult to reconcile the apparent discrepancy, it is possible that HMAs mediate their effects in more advanced levels of differentiation where cells become responsive to interferon, whereas, inter-individual variations in the process of RNA editing and, in particular, in the ADAR1/OAS/RNase L pathway may also confound the associations of clinical response with the induction of viral mimicry. Further ex vivo studies along with clinical correlations in well-annotated patient cohorts are warranted to decipher the role of ERE derepression in the antineoplastic mechanisms of HMAs. |
| first_indexed | 2024-12-22T05:29:01Z |
| format | Article |
| id | doaj.art-4828d488bc5e4afe9dfc707db12fa2b8 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-22T05:29:01Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-4828d488bc5e4afe9dfc707db12fa2b82022-12-21T18:37:30ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-03-011110.3389/fonc.2021.650473650473Mechanisms of Action of Hypomethylating Agents: Endogenous Retroelements at the EpicenterChryssoula KordellaEleftheria LamprianidouIoannis KotsianidisAbnormal DNA methylation patterns are thought to drive the pathobiology of high-risk myelodysplastic syndromes (HR-MDS) and acute myeloid leukemia (AML). Sixteen years after their initial approval, the hypomethylating agents (HMAs), 5-azacytidine (AZA) and 5-aza-2′-deoxycytidine, remain the mainstay of treatment for HR-MDS and AML. However, a connection of the hypomethylating or additional effects of HMAs with clinical responses remains yet to be shown, and the mode of action of HMAs remains obscure. Given the relatively short-lived responses and the inevitable development of resistance in HMAs, a thorough understanding of the antineoplastic mechanisms employed by HMAs holds critical importance. Recent data in cancer cell lines demonstrate that reactivation of endogenous retroelements (EREs) and induction of a cell-intrinsic antiviral response triggered by RNA neotranscripts may underlie the antitumor activity of HMAs. However, data on primary CD34+ cells derived from patients with HR-MDS failed to confirm a link between HMA-mediated ERE modulation and clinical response. Though difficult to reconcile the apparent discrepancy, it is possible that HMAs mediate their effects in more advanced levels of differentiation where cells become responsive to interferon, whereas, inter-individual variations in the process of RNA editing and, in particular, in the ADAR1/OAS/RNase L pathway may also confound the associations of clinical response with the induction of viral mimicry. Further ex vivo studies along with clinical correlations in well-annotated patient cohorts are warranted to decipher the role of ERE derepression in the antineoplastic mechanisms of HMAs.https://www.frontiersin.org/articles/10.3389/fonc.2021.650473/fullendogenous retroelementshypomethylating agents5-azacytidinedecitabinemyelodysplastic syndromesacute myeloid leukemia |
| spellingShingle | Chryssoula Kordella Eleftheria Lamprianidou Ioannis Kotsianidis Mechanisms of Action of Hypomethylating Agents: Endogenous Retroelements at the Epicenter Frontiers in Oncology endogenous retroelements hypomethylating agents 5-azacytidine decitabine myelodysplastic syndromes acute myeloid leukemia |
| title | Mechanisms of Action of Hypomethylating Agents: Endogenous Retroelements at the Epicenter |
| title_full | Mechanisms of Action of Hypomethylating Agents: Endogenous Retroelements at the Epicenter |
| title_fullStr | Mechanisms of Action of Hypomethylating Agents: Endogenous Retroelements at the Epicenter |
| title_full_unstemmed | Mechanisms of Action of Hypomethylating Agents: Endogenous Retroelements at the Epicenter |
| title_short | Mechanisms of Action of Hypomethylating Agents: Endogenous Retroelements at the Epicenter |
| title_sort | mechanisms of action of hypomethylating agents endogenous retroelements at the epicenter |
| topic | endogenous retroelements hypomethylating agents 5-azacytidine decitabine myelodysplastic syndromes acute myeloid leukemia |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.650473/full |
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