Hypomethylating Chemotherapeutic Agents as Therapy for Myelodysplastic Syndromes and Prevention of Acute Myeloid Leukemia

Sorrentino, Vincent G; Thota, Srijan; Gonzalez, Edward A.; Rameshwar, Pranela; Chang, Victor Tsu-Shih; Etchegaray, Jean‐Pierre

doi:10.3390/ph14070641

Cited by 20 publications

(8 citation statements)

References 174 publications

(317 reference statements)

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“…To identify genes that modulate decitabine’s anti-cancer activity in high-risk AML in an unbiased manner, we performed a genome-scale CRISPR genetic screen and integrated this data with multiomics measurements of decitabine response. Our results recapitulate multiple known factors which modulate response to decitabine, including DCK, SLC29A1, MCL1 and BCL2 15–18,9,19–21 , indicating the utility and robustness of our approach for interrogating the biology of decitabine in AML. Central to our study was the finding that epitranscriptomic RNA modification and RNA quality control pathways effectively modulate response to decitabine in AML.…”

Section: Introductionsupporting

confidence: 64%

“…Decitabine (5-aza-2’-deoxycytidine) is a pro-drug that is converted intracellularly into 5-aza-2’-deoxycytidine monophosphate 17,19,22 . This nucleoside analogue is in turn incorporated into DNA during replication, where it is thought to irreversibly and covalently trap and inhibit DNA methyltransferases DNMT1 / DNMT3A / DNMT3B (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…We validated that the resulting CRISPRi HL-60 cell line, hereafter referred to as HL-60i, is highly active for targeted gene knockdowns (Figure S1A). Decitabine (5-aza-2'-deoxycytidine) is a pro-drug that is converted intracellularly into 5-aza-2'deoxycytidine monophosphate 16,18,21 . This nucleoside analogue is in turn incorporated into DNA during replication, where it is thought to irreversibly and covalently trap and inhibit DNA methyltransferases DNMT1/DNMT3A/DNMT3B (Fig 1A).…”

Section: A Genome-wide Crispri Screen In Aml Cells Identifies Genes M...mentioning

confidence: 99%

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A multiomics approach reveals RNA dynamics promote cellular sensitivity to DNA hypomethylation

Arab

Dai

et al. 2022

Preprint

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The search for new approaches in cancer therapy requires a mechanistic understanding of cancer vulnerabilities and anti-cancer drug mechanisms of action. Problematically, some effective therapeutics target cancer vulnerabilities that we do not understand and have poorly defined mechanisms of anti-cancer activity. One such drug is decitabine, which is a frontline therapeutic approved for the treatment of high-risk acute myeloid leukemia (AML). Decitabine is thought to kill cancer cells selectively via inhibition of DNA methyltransferase enzymes, but the genes and mechanisms involved remain unclear. Here, we apply an integrated multiomics and CRISPR functional genomics approach to identify genes and processes associated with response to decitabine in AML cells. Our integrated multiomics approach reveals RNA dynamics are key regulators of DNA hypomethylation induced cell death. Specifically, regulation of RNA decapping, splicing and RNA methylation emerge as critical regulators of decitabine killing. Our results provide insights into the mechanisms of decitabine anti-cancer activity in treatment of AML and identify combination therapies which could potentiate decitabine anti-cancer activity.

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Section: Introductionsupporting

confidence: 64%

Section: Resultsmentioning

confidence: 99%

Section: A Genome-wide Crispri Screen In Aml Cells Identifies Genes M...mentioning

confidence: 99%

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A multiomics approach reveals RNA dynamics promote cellular sensitivity to DNA hypomethylation

Arab

Dai

et al. 2022

Preprint

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“…Our previous pilot study has shown that SPRED1 hypermethylation was related to some common AML gene mutations, such as DNMT3A and TET2 ( 14 ), which were response indicators for demethylation agents ( 26 , 27 ). However, in this study, hypermethylation of SPRED1 is more frequently presented in patients with an FLT3-ITD or NPM1 mutation, but not gene mutations involving DNA methylation, indicating that hypermethylation of SPRED1 might mediate resistance to drug by a more complex mechanism.…”

Section: Discussionmentioning

confidence: 99%

Methylation of SPRED1: A New Target in Acute Myeloid Leukemia

Wang

et al. 2022

Front. Oncol.

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Sprouty-related, EVH1 domain-containing protein 1 (SPRED1) has been identified as a novel tumor suppressor gene in acute myeloid leukemia (AML). Previous studies showed that SPRED1 methylation levels were significantly increased in AML patients, making it an interesting candidate for further investigations. To confirm the association of SPRED1 methylation, clinical parameters, and known molecular prognosticators and to identify the impact of methylation level on treatment outcome, we conducted this study in a larger cohort of 75 AML patients. Significantly increased methylation levels of SPRED1 were detected at four of ten CpG units by quantitative high-resolution mass spectrometry-based approach (MassARRAY) in AML patients. Whereas overall survival (OS) and relapse-free survival (RFS) showed no statistical difference between hypermethylation and hypomethylation subgroups, the relationship between methylation level and treatment response was indicated in paired samples from pre- and post-induction. To determine the possible mechanism of SPRED1 methylation in AML, we performed in vitro experiments using THP-1 cells, as the latter showed the highest methylation level (determined by utilizing bisulfite modification) among the three AML cell lines we tested. When treated with 5-AZA and lentivirus transfection, upregulated SPRED1 expression, decreased cell proliferation, increased cell differentiation and apoptosis, and inactivated phosphorylated extracellular signal-regulated kinase (p-ERK) were detected in THP-1 cells. These results show that demethylation of SPRED1 can inhibit the proliferation of AML cells and promote their differentiation and apoptosis, possibly by the ERK pathway. The hypermethylation of SPRED1 is a potential therapeutic target for AML.

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“…Decitabine (DEC) is known to exert an inhibitory effect on DNA methylation as well as block DNA replication and the induction of apoptosis [ 14 , 15 ]. Several studies confirmed that DEC targets 14,000 regulatory regions of genes in different cancer cell types as a DNA methyltransferase inhibitor (DNMTi) [ 16 ]. DEC demonstrates broad effects across most patient subgroups in various risk categories.…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Profiles Identify Biomarkers of Resistance to Decitabine in Myelodysplastic Syndromes

Kim

Shin

Kim

et al. 2021

Cells

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Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disease characterized by inefficient hematopoiesis and the potential development of acute leukemia. Among the most notable advances in the treatment of MDS is the hypomethylating agent, decitabine (5-aza-2′deoxycytidine). Although decitabine is well known as an effective method for treating MDS patients, only a subset of patients respond and a tolerance often develops, leading to treatment failure. Moreover, decitabine treatment is costly and causes unnecessary toxicity. Therefore, clarifying the mechanism of decitabine resistance is important for improving its therapeutic efficacy. To this end, we established a decitabine-resistant F-36P cell line from the parental F-36P leukemia cell line, and applied a genetic approach employing next-generation sequencing, various experimental techniques, and bioinformatics tools to determine differences in gene expression and relationships among genes. Thirty-eight candidate genes encoding proteins involved in decitabine-resistant-related pathways, including immune checkpoints, the regulation of myeloid cell differentiation, and PI3K-Akt signaling, were identified. Interestingly, two of the candidate genes, AKT3 and FOS, were overexpressed in MDS patients with poor prognoses. On the basis of these results, we are pursuing development of a gene chip for diagnosing decitabine resistance in MDS patients, with the goal of ultimately improving the power to predict treatment strategies and the prognosis of MDS patients.

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Hypomethylating Chemotherapeutic Agents as Therapy for Myelodysplastic Syndromes and Prevention of Acute Myeloid Leukemia

Cited by 20 publications

References 174 publications

A multiomics approach reveals RNA dynamics promote cellular sensitivity to DNA hypomethylation

A multiomics approach reveals RNA dynamics promote cellular sensitivity to DNA hypomethylation

Methylation of SPRED1: A New Target in Acute Myeloid Leukemia

Gene Expression Profiles Identify Biomarkers of Resistance to Decitabine in Myelodysplastic Syndromes

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