Tissue-Biased Expansion of DNMT3A-Mutant Clones in a Mosaic Individual Is Associated with Conserved Epigenetic Erosion

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2020 Jul 17

PMID 32673568

Citations 19

Authors

Ayala Tovy

Jaime M Reyes

Michael C Gundry

Lorenzo Brunetti

Henry Lee-Six

Mia Petljak

Hyun Jung Park

Anna G Guzman

Carina Rosas

Aaron R Jeffries

Emma Baple

Jonathan Mill

Andrew H Crosby

Valerie Sency

Baozhong Xin

Heather E Machado

Danielle Castillo

Jeffrey N Weitzel

Wei Li

Michael R Stratton

Peter J Campbell

Heng Wang

Mathijs A Sanders

Margaret A Goodell

Affiliations

Soon will be listed here.

Abstract

DNA methyltransferase 3A (DNMT3A) is the most commonly mutated gene in clonal hematopoiesis (CH). Somatic DNMT3A mutations arise in hematopoietic stem cells (HSCs) many years before malignancies develop, but difficulties in comparing their impact before malignancy with wild-type cells have limited the understanding of their contributions to transformation. To circumvent this limitation, we derived normal and DNMT3A mutant lymphoblastoid cell lines from a germline mosaic individual in whom these cells co-existed for nearly 6 decades. Mutant cells dominated the blood system, but not other tissues. Deep sequencing revealed similar mutational burdens and signatures in normal and mutant clones, while epigenetic profiling uncovered the focal erosion of DNA methylation at oncogenic regulatory regions in mutant clones. These regions overlapped with those sensitive to DNMT3A loss after DNMT3A ablation in HSCs and in leukemia samples. These results suggest that DNMT3A maintains a conserved DNA methylation pattern, the erosion of which provides a distinct competitive advantage to hematopoietic cells.

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References

Freed D, Stevens E, Pevsner J . Somatic mosaicism in the human genome. Genes (Basel). 2014; 5(4):1064-94. PMC: 4276927. DOI: 10.3390/genes5041064. View

Chalmers Z, Connelly C, Fabrizio D, Gay L, Ali S, Ennis R . Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017; 9(1):34. PMC: 5395719. DOI: 10.1186/s13073-017-0424-2. View

Xin B, Marino T, Szekely J, LeBlanc J, Cechner K, Sency V . Novel DNMT3A germline mutations are associated with inherited Tatton-Brown-Rahman syndrome. Clin Genet. 2016; 91(4):623-628. DOI: 10.1111/cge.12878. View

Alexandrov L, Jones P, Wedge D, Sale J, Campbell P, Nik-Zainal S . Clock-like mutational processes in human somatic cells. Nat Genet. 2015; 47(12):1402-7. PMC: 4783858. DOI: 10.1038/ng.3441. View

Zhang L, Dong X, Lee M, Maslov A, Wang T, Vijg J . Single-cell whole-genome sequencing reveals the functional landscape of somatic mutations in B lymphocytes across the human lifespan. Proc Natl Acad Sci U S A. 2019; 116(18):9014-9019. PMC: 6500118. DOI: 10.1073/pnas.1902510116. View

Yang L, Rodriguez B, Mayle A, Park H, Lin X, Luo M . DNMT3A Loss Drives Enhancer Hypomethylation in FLT3-ITD-Associated Leukemias. Cancer Cell. 2016; 29(6):922-934. PMC: 4908977. DOI: 10.1016/j.ccell.2016.05.003. View

Heinz S, Benner C, Spann N, Bertolino E, Lin Y, Laslo P . Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010; 38(4):576-89. PMC: 2898526. DOI: 10.1016/j.molcel.2010.05.004. View

Gilliland D, Griffin J . The roles of FLT3 in hematopoiesis and leukemia. Blood. 2002; 100(5):1532-42. DOI: 10.1182/blood-2002-02-0492. View

Jeong M, Park H, Celik H, Ostrander E, Reyes J, Guzman A . Loss of Dnmt3a Immortalizes Hematopoietic Stem Cells In Vivo. Cell Rep. 2018; 23(1):1-10. PMC: 5908249. DOI: 10.1016/j.celrep.2018.03.025. View

10.

Heyn H, Li N, Ferreira H, Moran S, Pisano D, Gomez A . Distinct DNA methylomes of newborns and centenarians. Proc Natl Acad Sci U S A. 2012; 109(26):10522-7. PMC: 3387108. DOI: 10.1073/pnas.1120658109. View

11.

Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N . The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25(16):2078-9. PMC: 2723002. DOI: 10.1093/bioinformatics/btp352. View

12.

Sanders M, Chew E, Flensburg C, Zeilemaker A, Miller S, Al Hinai A . MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML. Blood. 2018; 132(14):1526-1534. PMC: 6172562. DOI: 10.1182/blood-2018-05-852566. View

13.

Watson C, Papula A, Poon G, Wong W, Young A, Druley T . The evolutionary dynamics and fitness landscape of clonal hematopoiesis. Science. 2020; 367(6485):1449-1454. DOI: 10.1126/science.aay9333. View

14.

Mayle A, Yang L, Rodriguez B, Zhou T, Chang E, Curry C . Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation. Blood. 2014; 125(4):629-38. PMC: 4304108. DOI: 10.1182/blood-2014-08-594648. View

15.

Hou H, Kuo Y, Liu C, Chou W, Lee M, Chen C . DNMT3A mutations in acute myeloid leukemia: stability during disease evolution and clinical implications. Blood. 2011; 119(2):559-68. DOI: 10.1182/blood-2011-07-369934. View

16.

Jones D, Raine K, Davies H, Tarpey P, Butler A, Teague J . cgpCaVEManWrapper: Simple Execution of CaVEMan in Order to Detect Somatic Single Nucleotide Variants in NGS Data. Curr Protoc Bioinformatics. 2016; 56:15.10.1-15.10.18. PMC: 6097605. DOI: 10.1002/cpbi.20. View

17.

Tatton-Brown K, Seal S, Ruark E, Harmer J, Ramsay E, Del Vecchio Duarte S . Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat Genet. 2014; 46(4):385-8. PMC: 3981653. DOI: 10.1038/ng.2917. View

18.

Chen E, Tan C, Kou Y, Duan Q, Wang Z, Meirelles G . Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics. 2013; 14:128. PMC: 3637064. DOI: 10.1186/1471-2105-14-128. View

19.

Blokzijl F, de Ligt J, Jager M, Sasselli V, Roerink S, Sasaki N . Tissue-specific mutation accumulation in human adult stem cells during life. Nature. 2016; 538(7624):260-264. PMC: 5536223. DOI: 10.1038/nature19768. View

20.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View