The Evolution of Research and Therapy With Hypomethylating Agents in Acute Myeloid Leukemia and Myelodysplastic Syndrome: New Directions for Old Drugs

Short, Nicholas J.; Dombret, Hervé; Adès, Lionel; Kantarjian, Hagop M.

doi:10.1097/ppo.0000000000000568

Cited by 7 publications

(7 citation statements)

References 59 publications

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“…Hypermethylation of tumor suppressor genes is frequently observed in AML and plays a role in AML pathogenesis (24). Therapeutic agents targeting DNA methylation, such as the DNMT inhibitors azacitidine and decitabine, are widely used for the treatment of myelodysplastic syndrome and AML (26,27). The ZCCHC10 gene is located on chromosome 5q31.1 between PDLIM4 and VTRNA2-1, both of which play suppressive roles and are silenced by methylation in AML (12,13).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic silencing of ZCCHC10 by the lncRNA SNHG1 promotes progression and venetoclax resistance of acute myeloid leukemia

et al. 2023

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The gene encoding the tumor suppressor p53 is the most frequently mutated gene in cancers. However, p53 mutation is rare in acute myeloid leukemia (AML), and p53 is inactivated predominantly by aberrant expression of p53 regulators (such as MDM2). A previous study by the authors revealed that the ZCCHC10 protein suppressed MDM2-mediated degradation of the p53 protein in lung cancer. However, the expression and role of the ZCCHC10 gene in AML have not been investigated. In the present study, it was found that ZCCHC10 expression was downregulated in bone marrow samples of AML patients and that ZCCHC10 expression was significantly and negatively correlated with the expression of the lncRNA SNHG1. Suppression of SNHG1 decreased ZCCHC10 promoter methylation and increased ZCCHC10 expression. Notably, there is a putative binding motif in SNHG1 with full complementarity to five sites surrounding the CpG island in the ZCCHC10 promoter. Overexpression of wild-type SNHG1 promoted ZCCHC10 methylation, but overexpression of SNHG1 with deletion of the binding motif did not. Further study identified that SNHG1 simultaneously bound to the ZCCHC10 promoter and the DNA methyltransferases DNMT1 and DNMT3B. These results indicated that SNHG1 recruits DNMT1 and DNMT3B to the ZCCHC10 promoter, resulting in hypermethylation of the ZCCHC10 promoter. Kaplan-Meier survival analysis showed that ZCCHC10 expression was positively associated with overall survival in AML patients. In vitro experiments demonstrated that ZCCHC10 increased p53 expression and suppressed AML cell proliferation and survival. In the xenograft mouse model, ZCCHC10 decreased the proliferation of leukemic cells, improved the survival of leukemic mice, and increased sensitivity to the BCL inhibitor venetoclax. In conclusion, ZCCHC10 expression is suppressed by SNHG1-induced DNA methylation in AML. Downregulation of ZCCHC10 decreases p53 activation, promotes cell proliferation and survival, and thereby accelerates AML progression and the acquisition of venetoclax resistance. The present study identified a SNHG1/ZCCHC10/p53 signaling axis in AML that may be a therapeutic target in this malignancy.

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Section: Discussionmentioning

confidence: 99%

Epigenetic silencing of ZCCHC10 by the lncRNA SNHG1 promotes progression and venetoclax resistance of acute myeloid leukemia

et al. 2023

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“…[1][2][3][4][6][7][8][9][10][11]19,20 In the early 1990s, understanding the pathophysiology of methylation in cancer resulted in exploring decitabine as a hypomethylating agent (HMA) rather than as a classical cytotoxic chemotherapy drug. [22][23][24][25][26][27][28] This research resulted in the Food and Drug Administration approval of azacitidine and decitabine, in 2004 and 2006, respectively, for the treatment of myelodysplastic syndrome (MDS). [26][27][28] Similar research with these two HMAs resulted in their later approval in Europe for the treatment of older/unfit AML.…”

Section: Introductionmentioning

confidence: 99%

“…In the early 1990s, understanding the pathophysiology of methylation in cancer resulted in exploring decitabine as a hypomethylating agent (HMA) rather than as a classical cytotoxic chemotherapy drug 22–28 . This research resulted in the Food and Drug Administration approval of azacitidine and decitabine, in 2004 and 2006, respectively, for the treatment of myelodysplastic syndrome (MDS) 26–28 .…”

Section: Introductionmentioning

confidence: 99%

Prediction of survival with lower intensity therapy among older patients with acute myeloid leukemia

Sasaki

Ravandi

Kadia

et al. 2023

Cancer

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Background The aim of this study was to develop a prognostic model for survival in older/unfit patients with newly diagnosed acute myeloid leukemia (AML) who were treated with lower‐intensity chemotherapy regimens. Methods The authors reviewed all older/unfit patients with newly diagnosed AML who received lower‐intensity chemotherapy from 2000 until 2020 at their institution. A total of 1462 patients were included. They were divided (3:1 basis) into a training (n = 1088) and a validation group (n = 374). Results In the training cohort of 1088 patients (median age, 72 years), the multivariate analysis identified 11 consistent independent adverse factors associated with survival: older age, therapy‐related myeloid neoplasm, existence of previous myelodysplastic syndrome or myeloproliferative neoplasms, poor performance status, pulmonary comorbidity, anemia, thrombocytopenia, elevated lactate dehydrogenase, cytogenetic abnormalities, and the presence of infection at diagnosis, and therapy not containing venetoclax. The 3‐year survival rates were 52%, 24%, 10%, and 1% in favorable, intermediate, poor, and very poor risk, respectively. This survival model was validated in an independent cohort. In a subset of patients in whom molecular mutation profiles were performed in more recent times, adding the mutation profiles after accounting for the effects of previous factors identified IDH2 (favorable), NPM1 (favorable), and TP53 (unfavorable) mutations as molecular prognostic factors. Conclusion The proposed survival model with lower‐intensity chemotherapy in older/unfit patients with newly diagnosed AML may help to advise patients on their expected outcome, to propose different strategies in first complete remission, and to compare the results of different existing or future investigational therapies. Plain Language Summary Lower intensity therapy can be considered for older patients to avoid severe toxicities and adverse events. However, survival prediction in AML was commonly developed in patients who received intensive chemotherapy. In this study, we have proposed a survival model to guide therapeutic approach in older patients who received lower‐intensity therapy.

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“…However, with a growing understanding of their dose-dependent mechanisms of action and their important anti-leukemic epigenetic effects when given at lower doses, these agents were eventually studied at lower doses, which led to successful trials in MDS and AML. 8 In this review, we will discuss the development of azacitidine and decitabine in MDS and AML, highlighting the pivotal studies that led to their approval in these diseases. We will also review how these agents are being optimized in the current management of these diseases, including in novel combination therapies and with newer oral formulations.…”

Section: Introductionmentioning

confidence: 99%

“…Initial studies of these agents largely evaluated their higher cytotoxic doses. However, with a growing understanding of their dose‐dependent mechanisms of action and their important anti‐leukemic epigenetic effects when given at lower doses, these agents were eventually studied at lower doses, which led to successful trials in MDS and AML 8 . In this review, we will discuss the development of azacitidine and decitabine in MDS and AML, highlighting the pivotal studies that led to their approval in these diseases.…”

Section: Introductionmentioning

confidence: 99%

Hypomethylating agents for the treatment of myelodysplastic syndromes and acute myeloid leukemia: Past discoveries and future directions

Short

Kantarjian

2022

American J Hematol

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Azacitidine and decitabine are hypomethylating agents that have dose-dependent epigenetic and cytotoxic effects and are widely used in the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). In this review, we discuss the path to regulatory approval of azacitidine and decitabine, highlighting the substantial efforts that have been made to optimize the dosing schedule and administration of these drugs, including the development of new, oral formulations of both agents. We also review novel combination strategies that are being investigated in ongoing clinical trials for patients with MDS and AML, as well as efforts to expand the current indications of these agents.

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The Evolution of Research and Therapy With Hypomethylating Agents in Acute Myeloid Leukemia and Myelodysplastic Syndrome: New Directions for Old Drugs

Cited by 7 publications

References 59 publications

Epigenetic silencing of ZCCHC10 by the lncRNA SNHG1 promotes progression and venetoclax resistance of acute myeloid leukemia

Epigenetic silencing of ZCCHC10 by the lncRNA SNHG1 promotes progression and venetoclax resistance of acute myeloid leukemia

Prediction of survival with lower intensity therapy among older patients with acute myeloid leukemia

Hypomethylating agents for the treatment of myelodysplastic syndromes and acute myeloid leukemia: Past discoveries and future directions

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