title: Ordering of mutations in acute myeloid leukemia with partial tandem duplication of MLL (MLL-PTD).
abstract: Partial tandem duplication of MLL (MLL-PTD) characterizes acute myeloid leukemia (AML) patients often with a poor prognosis. To understand the order of occurrence of MLL-PTD in relation to other major AML mutations and to identify novel mutations that may be present in this unique AML molecular subtype, exome and targeted sequencing was performed on 85 MLL-PTD AML samples using HiSeq-2000. Genes involved in the cohesin complex (STAG2), a splicing factor (U2AF1) and a poorly studied gene, MGA were recurrently mutated, whereas NPM1, one of the most frequently mutated AML gene, was not mutated in MLL-PTD patients. Interestingly, clonality analysis suggests that IDH2/1, DNMT3A, U2AF1 and TET2 mutations are clonal and occur early, and MLL-PTD likely arises after these initial mutations. Conversely, proliferative mutations (FLT3, RAS), typically appear later, are largely subclonal and tend to be unstable. This study provides important insights for understanding the relative importance of different mutations for defining a targeted therapeutic strategy for MLL-PTD AML patients.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Q-Y
authors.initials: QY
authors.lastname: Sun
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: L-W
authors.initials: LW
authors.lastname: Ding
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: K-T
authors.initials: KT
authors.lastname: Tan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: W
authors.initials: W
authors.lastname: Chien
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: A
authors.initials: A
authors.lastname: Mayakonda
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.|Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA.
authors.forename: D-C
authors.initials: DC
authors.lastname: Lin
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: X-Y
authors.initials: XY
authors.lastname: Loh
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: J-F
authors.initials: JF
authors.lastname: Xiao
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Meggendorfer
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Alpermann
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: M
authors.initials: M
authors.lastname: Garg
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: S-L
authors.initials: SL
authors.lastname: Lim
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: V
authors.identifier: 0000-0001-7876-624X
authors.initials: V
authors.lastname: Madan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: N
authors.initials: N
authors.lastname: Hattori
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Nagata
authors.affiliation: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: A E J
authors.initials: AE
authors.lastname: Yeoh
authors.affiliation: Division of Hematology, National Taiwan University Hospital, National Taiwan University, Taiwan.
authors.forename: H-A
authors.initials: HA
authors.lastname: Hou
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Jiang
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: S
authors.initials: S
authors.lastname: Takao
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: L-Z
authors.initials: LZ
authors.lastname: Liu
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: S-Z
authors.initials: SZ
authors.lastname: Tan
authors.affiliation: Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lill
authors.affiliation: Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Pathology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kinoshita
authors.affiliation: Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, USA.
authors.forename: H M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Haferlach
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.|Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, USA.
authors.forename: H P
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D049109:Cell Proliferation / Q000235:genetics; D002999:Clone Cells; D059472:Exome; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D009154:Mutation; D059645:Mutation Rate; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D000090243:Nucleophosmin; D020080:Tandem Repeat Sequences; D013997:Time Factors
chemical_list: C497422:KMT2A protein, human; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase