Increased Local DNA Methylation Disorder in AMLs with DNMT3A-destabilizing Variants and Its Clinical Implication

Overview

Journal Nat Commun

Date 2025 Jan 10

PMID 39794314

Authors

Dohoon Lee

Bonil Koo

Seokhyeon Kim

Jamin Byun

Junshik Hong

Dong-Yeop Shin

Choong-Hyun Sun

Jaesung Kim

Ji-Joon Song

Siddhartha Jaiswal

Sung-Soo Yoon

Sun Kim

Youngil Koh

Affiliations

Soon will be listed here.

Abstract

The mechanistic link between the complex mutational landscape of de novo methyltransferase DNMT3A and the pathology of acute myeloid leukemia (AML) has not been clearly elucidated so far. Motivated by a recent discovery of the significance of DNMT3A-destabilizing mutations (DNMT3A) in AML, we here investigate the common characteristics of DNMT3A AML methylomes through computational analyses. We present that methylomes of DNMT3A AMLs are considerably different from those of DNMT3A AMLs in that they exhibit increased intratumor DNA methylation heterogeneity in bivalent chromatin domains. This epigenetic heterogeneity was associated with the transcriptional variability of developmental and membrane-associated factors shaping stem cell niche, and also was a predictor of the response of AML cells to hypomethylating agents, implying that the survival of AML cells depends on stochastic DNA methylations at bivalent domains. Altogether, our work provides a novel mechanistic model suggesting the genomic origin of the aberrant epigenomic heterogeneity in disease conditions.

References

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

Sigalotti L, Fratta E, Coral S, Cortini E, Covre A, Nicolay H . Epigenetic drugs as pleiotropic agents in cancer treatment: biomolecular aspects and clinical applications. J Cell Physiol. 2007; 212(2):330-44. DOI: 10.1002/jcp.21066. View

Jeong M, Sun D, Luo M, Huang Y, Challen G, Rodriguez B . Large conserved domains of low DNA methylation maintained by Dnmt3a. Nat Genet. 2013; 46(1):17-23. PMC: 3920905. DOI: 10.1038/ng.2836. View

Kordella C, Lamprianidou E, Kotsianidis I . Mechanisms of Action of Hypomethylating Agents: Endogenous Retroelements at the Epicenter. Front Oncol. 2021; 11:650473. PMC: 7985079. DOI: 10.3389/fonc.2021.650473. View

Lee D, Koo B, Yang J, Kim S . Metheor: Ultrafast DNA methylation heterogeneity calculation from bisulfite read alignments. PLoS Comput Biol. 2023; 19(3):e1010946. PMC: 10062925. DOI: 10.1371/journal.pcbi.1010946. View

Cingolani P, Platts A, Wang L, Coon M, Nguyen T, Wang L . A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin). 2012; 6(2):80-92. PMC: 3679285. DOI: 10.4161/fly.19695. View

Rajavelu A, Jurkowska R, Fritz J, Jeltsch A . Function and disruption of DNA methyltransferase 3a cooperative DNA binding and nucleoprotein filament formation. Nucleic Acids Res. 2011; 40(2):569-80. PMC: 3258144. DOI: 10.1093/nar/gkr753. View

Kuleshov M, Jones M, Rouillard A, Fernandez N, Duan Q, Wang Z . Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016; 44(W1):W90-7. PMC: 4987924. DOI: 10.1093/nar/gkw377. View

Huang J, Nguyen-McCarty M, Hexner E, Danet-Desnoyers G, Klein P . Maintenance of hematopoietic stem cells through regulation of Wnt and mTOR pathways. Nat Med. 2012; 18(12):1778-85. PMC: 3518679. DOI: 10.1038/nm.2984. View

10.

Ernst J, Kellis M . Chromatin-state discovery and genome annotation with ChromHMM. Nat Protoc. 2017; 12(12):2478-2492. PMC: 5945550. DOI: 10.1038/nprot.2017.124. View

11.

Ghandi M, Huang F, Jane-Valbuena J, Kryukov G, Lo C, McDonald 3rd E . Next-generation characterization of the Cancer Cell Line Encyclopedia. Nature. 2019; 569(7757):503-508. PMC: 6697103. DOI: 10.1038/s41586-019-1186-3. View

12.

Vaisvila R, Ponnaluri V, Sun Z, Langhorst B, Saleh L, Guan S . Enzymatic methyl sequencing detects DNA methylation at single-base resolution from picograms of DNA. Genome Res. 2021; 31(7):1280-1289. PMC: 8256858. DOI: 10.1101/gr.266551.120. View

13.

Russler-Germain D, Spencer D, Young M, Lamprecht T, Miller C, Fulton R . The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. Cancer Cell. 2014; 25(4):442-54. PMC: 4018976. DOI: 10.1016/j.ccr.2014.02.010. View

14.

Gowher H, Jeltsch A . Enzymatic properties of recombinant Dnmt3a DNA methyltransferase from mouse: the enzyme modifies DNA in a non-processive manner and also methylates non-CpG [correction of non-CpA] sites. J Mol Biol. 2001; 309(5):1201-8. DOI: 10.1006/jmbi.2001.4710. View

15.

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

16.

Fleming H, Janzen V, Lo Celso C, Guo J, Leahy K, Kronenberg H . Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell. 2008; 2(3):274-83. PMC: 2991120. DOI: 10.1016/j.stem.2008.01.003. View

17.

Li S, Garrett-Bakelman F, Chung S, Sanders M, Hricik T, Rapaport F . Distinct evolution and dynamics of epigenetic and genetic heterogeneity in acute myeloid leukemia. Nat Med. 2016; 22(7):792-9. PMC: 4938719. DOI: 10.1038/nm.4125. View

18.

Frankish A, Diekhans M, Jungreis I, Lagarde J, Loveland J, Mudge J . GENCODE 2021. Nucleic Acids Res. 2020; 49(D1):D916-D923. PMC: 7778937. DOI: 10.1093/nar/gkaa1087. View

19.

Sheffield N, Pierron G, Klughammer J, Datlinger P, Schonegger A, Schuster M . DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma. Nat Med. 2017; 23(3):386-395. PMC: 5951283. DOI: 10.1038/nm.4273. View

20.

Cole C, Russler-Germain D, Ketkar S, Verdoni A, Smith A, Bangert C . Haploinsufficiency for DNA methyltransferase 3A predisposes hematopoietic cells to myeloid malignancies. J Clin Invest. 2017; 127(10):3657-3674. PMC: 5617681. DOI: 10.1172/JCI93041. View