title: DNMT3A mutation leads to leukemic extramedullary infiltration mediated by TWIST1.
abstract: DNMT3A mutations are frequently discovered in acute myeloid leukemia (AML), associated with poor outcome. Recently, a relapse case report of AML extramedullary disease has showed that AML cells harboring DNMT3A variation were detected in the cerebral spinal fluid. However, whether a causal relationship exists between DNMT3A mutation (D3Amut) and extramedullary infiltration (EMI) is unclear.
  
  
  
  We took advantage of DNMT3A (R882C) mutation-carrying AML cell strain, that is, OCI-AML3, assessing its migration ability in vitro and in vivo. By RNA interfering technology and a xenograft mouse model, we evaluated the effect of DNMT3A mutation on cell mobility and explored the possible mechanism.
  
  
  
  OCI-AML3 displayed extraordinary migration ability in vitro and infiltrated into meninges of NOD/SCID mice after intravenous transfusion. We found that this leukemic migration or infiltration capacity was significantly compromised by the knockdown of DNMT3A mutant. Notably, TWIST1, a critical inducer of epithelial-mesenchymal transition, which underlies the metastasis of carcinomas, was highly expressed in association with R882 mutations. Abrogation of TWIST1 in DNMT3A mutated cells considerably weakened their mobility or infiltration.
  
  
  
  Our results demonstrate that D3Amut in OCI-AML3 strain enhances leukemic aggressiveness by promoting EMI process, which is partially through upregulating TWIST1.
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin Er Road, Shanghai, 200025, China. nbxujie1011@163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin Er Road, Shanghai, 200025, China.
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Hematology, the First Hospital of China Medical University, Shenyang, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Yan
authors.affiliation: Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.|Department of Bioinformatics, School of Life Sciences and Technology, Tong-Ji University, Shanghai, China.
authors.forename: Xue-Qiu
authors.initials: XQ
authors.lastname: Lin
authors.affiliation: Division of Biostatistics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin Er Road, Shanghai, 200025, China.
authors.forename: Jian-Qing
authors.initials: JQ
authors.lastname: Mi
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin Er Road, Shanghai, 200025, China.
authors.forename: Jun-Min
authors.initials: JM
authors.lastname: Li
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin Er Road, Shanghai, 200025, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin Er Road, Shanghai, 200025, China.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 197 Rui-Jin Er Road, Shanghai, 200025, China. sjchen@stn.sh.cn.
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D058750:Epithelial-Mesenchymal Transition; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000235:genetics; D009687:Nuclear Proteins / Q000032:analysis / Q000502:physiology*; D051879:Twist-Related Protein 1 / Q000032:analysis / Q000502:physiology*
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: Acute myeloid leukemia; DNMT3A mutation; Extramedullary infiltration; TWIST1