DNA Methylation Landscape Reveals GNAS As a Decitabine-responsive Marker in Patients with Acute Myeloid Leukemia

Overview

Journal Neoplasia

Publisher Elsevier

Specialty Oncology

Date 2024 Jan 21

PMID 38245923

Authors

Shujiao He

Yan Li

Lei Wang

Yisheng Li

Lu Xu

Diya Cai

Jingfeng Zhou

Li Yu

Affiliations

Soon will be listed here.

Abstract

Background: The demethylation agent decitabine (DAC) is a pivotal non-intensive alternative treatment for acute myeloid leukemia (AML). However, patient responses to DAC are highly variable, and predictive biomarkers are warranted. Herein, the DNA methylation landscape of patients treated with a DAC-based combination regimen was compared with that of patients treated with standard chemotherapy to develop a molecular approach for predicting clinical response to DAC.

Methods: Twenty-five non-M3 AML patients were enrolled and subjected to DNA methylation sequencing and profiling to identify differentially methylated regions (DMRs) and genes of interest. Moreover, the effects of a DAC-based regimen on apoptosis and gene expression were explored using Kasumi-1 and K562 cells.

Results: Overall, we identified 541 DMRs that were specifically responsive to DAC, among which 172 DMRs showed hypomethylation patterns upon treatment and were aligned with the promoter regions of 182 genes. In particular, GNAS was identified as a critical DAC-responsive gene, with in vitro GNAS downregulation leading to reduced cell apoptosis induced by DAC and cytarabine combo treatment.

Conclusions: We found that GNAS is a DAC-sensitive gene in AML and may serve as a prognostic biomarker to assess the responsiveness of patients with AML to DAC-based therapy.

References

Qin T, Youssef E, Jelinek J, Chen R, Yang A, Garcia-Manero G . Effect of cytarabine and decitabine in combination in human leukemic cell lines. Clin Cancer Res. 2007; 13(14):4225-32. DOI: 10.1158/1078-0432.CCR-06-2762. View

Allum F, Hedman A, Shao X, Cheung W, Vijay J, Guenard F . Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements. Nat Commun. 2019; 10(1):1209. PMC: 6418220. DOI: 10.1038/s41467-019-09184-z. View

Li Y, Zhao H, Xu Q, Lv N, Jing Y, Wang L . Detection of prognostic methylation markers by methylC-capture sequencing in acute myeloid leukemia. Oncotarget. 2018; 8(66):110444-110459. PMC: 5746395. DOI: 10.18632/oncotarget.22789. View

Cong Q, Liu Y, Zhou T, Zhou Y, Xu R, Cheng C . A self-amplifying loop of YAP and SHH drives formation and expansion of heterotopic ossification. Sci Transl Med. 2021; 13(599). PMC: 8638088. DOI: 10.1126/scitranslmed.abb2233. View

Feng P, Zhang J, Zhang J, Liu X, Pan L, Chen D . Deacetylation of YAP1 Promotes the Resistance to Chemo- and Targeted Therapy in FLT3-ITD AML Cells. Front Cell Dev Biol. 2022; 10:842214. PMC: 9152322. DOI: 10.3389/fcell.2022.842214. View

Kantarjian H, Thomas X, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J . Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012; 30(21):2670-7. PMC: 4874148. DOI: 10.1200/JCO.2011.38.9429. View

Yang X, Han H, De Carvalho D, Lay F, Jones P, Liang G . Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell. 2014; 26(4):577-90. PMC: 4224113. DOI: 10.1016/j.ccr.2014.07.028. View

Baylin S, Bestor T . Altered methylation patterns in cancer cell genomes: cause or consequence?. Cancer Cell. 2002; 1(4):299-305. DOI: 10.1016/s1535-6108(02)00061-2. View

Leonard S, Perry T, Woodman C, Kearns P . Sequential treatment with cytarabine and decitabine has an increased anti-leukemia effect compared to cytarabine alone in xenograft models of childhood acute myeloid leukemia. PLoS One. 2014; 9(1):e87475. PMC: 3905025. DOI: 10.1371/journal.pone.0087475. View

10.

Khan N, Hantel A, Knoebel R, Artz A, Larson R, Godley L . Efficacy of single-agent decitabine in relapsed and refractory acute myeloid leukemia. Leuk Lymphoma. 2017; 58(9):1-7. DOI: 10.1080/10428194.2017.1289524. View

11.

Xu W, Li J, Rong B, Zhao B, Wang M, Dai R . Correction to: DNMT3A reads and connects histone H3K36me2 to DNA methylation. Protein Cell. 2019; 11(3):230. PMC: 7026214. DOI: 10.1007/s13238-019-00678-6. View

12.

Huang S, Jiang M, Chen G, Qian K, Gao H, Guan W . Epigenetic Silencing of Eyes Absent 4 Gene by Acute Myeloid Leukemia 1-Eight-twenty-one Oncoprotein Contributes to Leukemogenesis in t(8;21) Acute Myeloid Leukemia. Chin Med J (Engl). 2016; 129(11):1355-62. PMC: 4894048. DOI: 10.4103/0366-6999.182838. View

13.

Meyer T, Jahn N, Lindner S, Rohner L, Dolnik A, Weber D . Functional characterization of BRCC3 mutations in acute myeloid leukemia with t(8;21)(q22;q22.1). Leukemia. 2019; 34(2):404-415. PMC: 7214237. DOI: 10.1038/s41375-019-0578-6. View

14.

Juhling F, Kretzmer H, Bernhart S, Otto C, Stadler P, Hoffmann S . metilene: fast and sensitive calling of differentially methylated regions from bisulfite sequencing data. Genome Res. 2015; 26(2):256-62. PMC: 4728377. DOI: 10.1101/gr.196394.115. View

15.

Kelly A, Madzo J, Madireddi P, Kropf P, Good C, Jelinek J . Demethylator phenotypes in acute myeloid leukemia. Leukemia. 2018; 32(10):2178-2188. PMC: 6128790. DOI: 10.1038/s41375-018-0084-2. View

16.

Coles G, Cristea S, Webber J, Levin R, Moss S, He A . Unbiased Proteomic Profiling Uncovers a Targetable GNAS/PKA/PP2A Axis in Small Cell Lung Cancer Stem Cells. Cancer Cell. 2020; 38(1):129-143.e7. PMC: 7363571. DOI: 10.1016/j.ccell.2020.05.003. View

17.

Hollstein P, Shaw R . GNAS shifts metabolism in pancreatic cancer. Nat Cell Biol. 2018; 20(7):740-741. DOI: 10.1038/s41556-018-0120-5. View

18.

Ferrara F, Lessi F, Vitagliano O, Birkenghi E, Rossi G . Current Therapeutic Results and Treatment Options for Older Patients with Relapsed Acute Myeloid Leukemia. Cancers (Basel). 2019; 11(2). PMC: 6406399. DOI: 10.3390/cancers11020224. View

19.

Afolabi H, Salleh S, Zakaria Z, Chng E, Nafi S, Aziz A . A GNAS Gene Mutation's Independent Expression in the Growth of Colorectal Cancer: A Systematic Review and Meta-Analysis. Cancers (Basel). 2022; 14(22). PMC: 9688108. DOI: 10.3390/cancers14225480. View

20.

Kunde-Ramamoorthy G, Coarfa C, Laritsky E, Kessler N, Harris R, Xu M . Comparison and quantitative verification of mapping algorithms for whole-genome bisulfite sequencing. Nucleic Acids Res. 2014; 42(6):e43. PMC: 3973287. DOI: 10.1093/nar/gkt1325. View