Literature DB >> 28461508

Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement.

Yu-Jun Dai1, Yue-Ying Wang2, Jin-Yan Huang1, Li Xia1, Xiao-Dong Shi1, Jie Xu1, Jing Lu1, Xian-Bin Su3, Ying Yang1, Wei-Na Zhang1, Pan-Pan Wang1, Song-Fang Wu1, Ting Huang1, Jian-Qing Mi1, Ze-Guang Han3, Zhu Chen2,3, Sai-Juan Chen2,3.   

Abstract

DNMT3A is frequently mutated in acute myeloid leukemia (AML). To explore the features of human AML with the hotspot DNMT3A R882H mutation, we generated Dnmt3a R878H conditional knockin mice, which developed AML with enlarged Lin-Sca1+cKit+ cell compartments. The transcriptome and DNA methylation profiling of bulk leukemic cells and the single-cell RNA sequencing of leukemic stem/progenitor cells revealed significant changes in gene expression and epigenetic regulatory patterns that cause differentiation arrest and growth advantage. Consistent with leukemic cell accumulation in G2/M phase, CDK1 was up-regulated due to mTOR activation associated with DNA hypomethylation. Overexpressed CDK1-mediated EZH2 phosphorylation resulted in an abnormal trimethylation of H3K27 profile. The mTOR inhibitor rapamycin elicited a significant therapeutic response in Dnmt3aR878H/WT mice.

Entities:  

Keywords:  Dnmt3a R878H mutation; conditional knockin mice; leukemia; mTOR inhibitor; single-cell RNA-seq

Mesh：

Substances：

Year:  2017        PMID： 28461508      PMCID： PMC5441829          DOI： 10.1073/pnas.1703476114

Source DB:  PubMed          Journal:  Proc Natl Acad Sci U S A        ISSN： 0027-8424            Impact factor:   11.205


  30 in total

1.  Dnmt3L antagonizes DNA methylation at bivalent promoters and favors DNA methylation at gene bodies in ESCs.

Authors:  Francesco Neri; Anna Krepelova; Danny Incarnato; Mara Maldotti; Caterina Parlato; Federico Galvagni; Filomena Matarese; Hendrik G Stunnenberg; Salvatore Oliviero
Journal:  Cell       Date:  2013-09-26       Impact factor: 41.582

2.  The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers.

Authors:  David A Russler-Germain; David H Spencer; Margaret A Young; Tamara L Lamprecht; Christopher A Miller; Robert Fulton; Matthew R Meyer; Petra Erdmann-Gilmore; R Reid Townsend; Richard K Wilson; Timothy J Ley
Journal:  Cancer Cell       Date:  2014-03-20       Impact factor: 31.743

3.  Critical role of arachidonic acid-activated mTOR signaling in breast carcinogenesis and angiogenesis.

Authors:  Z-H Wen; Y-C Su; P-L Lai; Y Zhang; Y-F Xu; A Zhao; G-Y Yao; C-H Jia; J Lin; S Xu; L Wang; X-K Wang; A-L Liu; Y Jiang; Y-F Dai; X-C Bai
Journal:  Oncogene       Date:  2012-02-20       Impact factor: 9.867

4.  DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling.

Authors:  Olga A Guryanova; Kaitlyn Shank; Barbara Spitzer; Luisa Luciani; Richard P Koche; Francine E Garrett-Bakelman; Chezi Ganzel; Benjamin H Durham; Abhinita Mohanty; Gregor Hoermann; Sharon A Rivera; Alan G Chramiec; Elodie Pronier; Lennart Bastian; Matthew D Keller; Daniel Tovbin; Evangelia Loizou; Abby R Weinstein; Adriana Rodriguez Gonzalez; Yen K Lieu; Jacob M Rowe; Friederike Pastore; Anna Sophia McKenney; Andrei V Krivtsov; Wolfgang R Sperr; Justin R Cross; Christopher E Mason; Martin S Tallman; Maria E Arcila; Omar Abdel-Wahab; Scott A Armstrong; Stefan Kubicek; Philipp B Staber; Mithat Gönen; Elisabeth M Paietta; Ari M Melnick; Stephen D Nimer; Siddhartha Mukherjee; Ross L Levine
Journal:  Nat Med       Date:  2016-11-14       Impact factor: 53.440

5.  Dnmt3a loss predisposes murine hematopoietic stem cells to malignant transformation.

Authors:  Allison Mayle; Liubin Yang; Benjamin Rodriguez; Ting Zhou; Edmund Chang; Choladda V Curry; Grant A Challen; Wei Li; David Wheeler; Vivienne I Rebel; Margaret A Goodell
Journal:  Blood       Date:  2015-01-22       Impact factor: 22.113

6.  DNMT3A mutations in acute myeloid leukemia.

Authors:  Timothy J Ley; Li Ding; Matthew J Walter; Michael D McLellan; Tamara Lamprecht; David E Larson; Cyriac Kandoth; Jacqueline E Payton; Jack Baty; John Welch; Christopher C Harris; Cheryl F Lichti; R Reid Townsend; Robert S Fulton; David J Dooling; Daniel C Koboldt; Heather Schmidt; Qunyuan Zhang; John R Osborne; Ling Lin; Michelle O'Laughlin; Joshua F McMichael; Kim D Delehaunty; Sean D McGrath; Lucinda A Fulton; Vincent J Magrini; Tammi L Vickery; Jasreet Hundal; Lisa L Cook; Joshua J Conyers; Gary W Swift; Jerry P Reed; Patricia A Alldredge; Todd Wylie; Jason Walker; Joelle Kalicki; Mark A Watson; Sharon Heath; William D Shannon; Nobish Varghese; Rakesh Nagarajan; Peter Westervelt; Michael H Tomasson; Daniel C Link; Timothy A Graubert; John F DiPersio; Elaine R Mardis; Richard K Wilson
Journal:  N Engl J Med       Date:  2010-11-10       Impact factor: 91.245

7.  Loss of Dnmt3b accelerates MLL-AF9 leukemia progression.

Authors:  Y Zheng; H Zhang; Y Wang; X Li; P Lu; F Dong; Y Pang; S Ma; H Cheng; S Hao; F Tang; W Yuan; X Zhang; T Cheng
Journal:  Leukemia       Date:  2016-05-02       Impact factor: 11.528

8.  DNMT3A Arg882 mutation drives chronic myelomonocytic leukemia through disturbing gene expression/DNA methylation in hematopoietic cells.

Authors:  Jie Xu; Yue-Ying Wang; Yu-Jun Dai; Wu Zhang; Wei-Na Zhang; Shu-Min Xiong; Zhao-Hui Gu; Kan-Kan Wang; Rong Zeng; Zhu Chen; Sai-Juan Chen
Journal:  Proc Natl Acad Sci U S A       Date:  2014-02-04       Impact factor: 11.205

9.  mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert).

Authors:  Joseph T Rodgers; Katherine Y King; Jamie O Brett; Melinda J Cromie; Gregory W Charville; Katie K Maguire; Christopher Brunson; Namrata Mastey; Ling Liu; Chang-Ru Tsai; Margaret A Goodell; Thomas A Rando
Journal:  Nature       Date:  2014-05-25       Impact factor: 49.962

10.  DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells.

Authors:  Xiaotian Zhang; Jianzhong Su; Mira Jeong; Myunggon Ko; Yun Huang; Hyun Jung Park; Anna Guzman; Yong Lei; Yung-Hsin Huang; Anjana Rao; Wei Li; Margaret A Goodell
Journal:  Nat Genet       Date:  2016-07-18       Impact factor: 38.330
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  22 in total

1.  Single-cell multi-omics of human clonal hematopoiesis reveals that DNMT3A R882 mutations perturb early progenitor states through selective hypomethylation.

Authors:  Anna S Nam; Neville Dusaj; Franco Izzo; Rekha Murali; Robert M Myers; Tarek H Mouhieddine; Jesus Sotelo; Salima Benbarche; Michael Waarts; Federico Gaiti; Sabrin Tahri; Ross Levine; Omar Abdel-Wahab; Lucy A Godley; Ronan Chaligne; Irene Ghobrial; Dan A Landau
Journal:  Nat Genet       Date:  2022-09-22       Impact factor: 41.307

Review 2.  Clonal Hematopoiesis and Evolution to Hematopoietic Malignancies.

Authors:  Robert L Bowman; Lambert Busque; Ross L Levine
Journal:  Cell Stem Cell       Date:  2018-02-01       Impact factor: 24.633

Review 3.  Histone Methyltransferase EZH2: A Therapeutic Target for Ovarian Cancer.

Authors:  Bayley A Jones; Sooryanarayana Varambally; Rebecca C Arend
Journal:  Mol Cancer Ther       Date:  2018-03       Impact factor: 6.261

4.  Single-Cell Gene Expression Analyses Reveal Distinct Self-Renewing and Proliferating Subsets in the Leukemia Stem Cell Compartment in Acute Myeloid Leukemia.

Authors:  Karen Sachs; Aaron L Sarver; Klara E Noble-Orcutt; Rebecca S LaRue; Marie Lue Antony; Daniel Chang; Yoonkyu Lee; Connor M Navis; Alexandria L Hillesheim; Ian R Nykaza; Ngoc A Ha; Conner J Hansen; Fatma K Karadag; Rachel J Bergerson; Michael R Verneris; Matthew M Meredith; Matthew L Schomaker; Michael A Linden; Chad L Myers; David A Largaespada; Zohar Sachs
Journal:  Cancer Res       Date:  2019-11-29       Impact factor: 12.701

5.  The R882H DNMT3A hot spot mutation stabilizes the formation of large DNMT3A oligomers with low DNA methyltransferase activity.

Authors:  Tuong-Vi Nguyen; Shihua Yao; Yahong Wang; Alan Rolfe; Anand Selvaraj; Rachel Darman; Jiyuan Ke; Markus Warmuth; Peter G Smith; Nicholas A Larsen; Lihua Yu; Ping Zhu; Peter Fekkes; Frédéric H Vaillancourt; David M Bolduc
Journal:  J Biol Chem       Date:  2019-10-03       Impact factor: 5.157

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

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
Journal:  Cell Stem Cell       Date:  2020-07-15       Impact factor: 24.633

7.  Study on the Immune Escape Mechanism of Acute Myeloid Leukemia With DNMT3A Mutation.

Authors:  Yimei Que; Huimin Li; Liman Lin; Xiaojian Zhu; Min Xiao; Ying Wang; Li Zhu; Dengju Li
Journal:  Front Immunol       Date:  2021-05-20       Impact factor: 7.561

8.  DNMT3A Mutation-Induced CDK1 Overexpression Promotes Leukemogenesis by Modulating the Interaction between EZH2 and DNMT3A.

Authors:  Ying Yang; Yujun Dai; Xuejiao Yang; Songfang Wu; Yueying Wang
Journal:  Biomolecules       Date:  2021-05-22

Review 9.  Clonal hematopoiesis and its emerging effects on cellular therapies.

Authors:  Malte von Bonin; Helena Klara Jambor; Raphael Teipel; Friedrich Stölzel; Christian Thiede; Frederik Damm; Frank Kroschinsky; Johannes Schetelig; Triantafyllos Chavakis; Martin Bornhäuser
Journal:  Leukemia       Date:  2021-07-02       Impact factor: 11.528

Review 10.  Alterations to DNMT3A in Hematologic Malignancies.

Authors:  Kartika Venugopal; Yang Feng; Daniil Shabashvili; Olga A Guryanova
Journal:  Cancer Res       Date:  2020-10-21       Impact factor: 13.312
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