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

Cell Stem Cell
Ayala TovyMargaret A Goodell

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.

References

Aug 15, 2002·Blood·D Gary Gilliland, James D Griffin
Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Jun 10, 2009·Bioinformatics·Heng LiUNKNOWN 1000 Genome Project Data Processing Subgroup
Jan 23, 2010·Science·Matthew P McCormackDavid J Curtis
Jul 6, 2010·Nucleic Acids Research·Kai WangHakon Hakonarson
Nov 12, 2010·The New England Journal of Medicine·Timothy J LeyRichard K Wilson
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
Dec 6, 2011·Nature Genetics·Grant A ChallenMargaret A Goodell
Mar 6, 2012·Nature Methods·Ben Langmead, Steven L Salzberg
Apr 12, 2012·Blood·Ana Flávia Tibúrcio RibeiroRuud Delwel
Jun 13, 2012·Proceedings of the National Academy of Sciences of the United States of America·Holger HeynManel Esteller
Aug 31, 2012·Science Translational Medicine·Max JanRavindra Majeti
Apr 17, 2013·BMC Bioinformatics·Edward Y ChenAvi Ma'ayan
Nov 26, 2013·Nature Genetics·Mira JeongMargaret A Goodell
Jul 25, 2014·Disease Models & Mechanisms·Carolyn S Grove, George S Vassiliou
Aug 19, 2014·Cell Stem Cell·Grant A ChallenMargaret A Goodell
Nov 27, 2014·The New England Journal of Medicine·Siddhartha JaiswalBenjamin L Ebert
Dec 17, 2014·Genes·Donald FreedJonathan Pevsner
Feb 20, 2015·Nature Reviews. Cancer·Liubin YangMargaret A Goodell
Nov 10, 2015·Nature Genetics·Ludmil B AlexandrovMichael R Stratton
Jun 15, 2016·Cancer Cell·Liubin YangMargaret A Goodell
Oct 5, 2016·Nature·Francis BlokzijlRuben van Boxtel
Dec 9, 2016·Current Protocols in Bioinformatics·David JonesPeter J Campbell
Dec 23, 2016·Cold Spring Harbor Perspectives in Medicine·Lorenzo BrunettiMargaret A Goodell
Feb 10, 2017·Blood·Raman SoodPaul Liu
Apr 20, 2017·Genome Medicine·Zachary R ChalmersGarrett M Frampton
Apr 26, 2017·Nature Communications·Feng PanMingjiang Xu
May 4, 2017·Proceedings of the National Academy of Sciences of the United States of America·Yu-Jun DaiSai-Juan Chen
Dec 1, 2017·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Jeffrey N WeitzelKory Jasperson
Apr 5, 2018·Cell Reports·Mira JeongGrant A Challen
Sep 7, 2018·Nature·Henry Lee-SixPeter J Campbell
Apr 18, 2019·Proceedings of the National Academy of Sciences of the United States of America·Lei ZhangJan Vijg
Jul 7, 2019·Nature Communications·Francesco MauraNiccolò Bolli

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Citations

Oct 23, 2020·Cancer Research·Kartika VenugopalOlga A Guryanova
Jan 30, 2021·Seminars in Hematology·Sriram SundaravelAmittha Wickrema
May 11, 2021·The Journal of Experimental Medicine·Jung-Yeon LimMinji Byun
Aug 9, 2020·Cell Stem Cell·L Alexander LiggettVijay G Sankaran
Jul 29, 2021·Nature Communications·Amanda M SmithTimothy J Ley
Aug 19, 2021·Best Practice & Research. Clinical Haematology·Fernanda Gutierrez-RodriguesNeal S Young
Nov 18, 2021·Science Translational Medicine·Brooke PrinzingGiedre Krenciute

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