title: Comprehensive mutational analysis of primary and relapse acute promyelocytic leukemia.
abstract: Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: V
authors.initials: V
authors.lastname: Madan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: P
authors.initials: P
authors.lastname: Shyamsunder
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: L
authors.initials: L
authors.lastname: Han
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: A
authors.initials: A
authors.lastname: Mayakonda
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: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: J
authors.initials: J
authors.lastname: Sundaresan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: D
authors.initials: D
authors.lastname: Kanojia
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, India.
authors.forename: S
authors.initials: S
authors.lastname: Ganesan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: N
authors.initials: N
authors.lastname: Hattori
authors.affiliation: Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: N
authors.initials: N
authors.lastname: Fulton
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: Munich Leukemia Laboratory (MLL), Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Alpermann
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
authors.forename: M-C
authors.initials: MC
authors.lastname: Kuo
authors.affiliation: Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: S
authors.initials: S
authors.lastname: Rostami
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: J
authors.initials: J
authors.lastname: Matthews
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sanada
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: Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Laboratory of DNA Information 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: Department of Haematology, Christian Medical College, Vellore, India.
authors.forename: E
authors.initials: E
authors.lastname: Chendamarai
authors.affiliation: Department of Internal Medicine, National Taiwan University, Medical College and Hospital, Taipei, Taiwan.
authors.forename: H-A
authors.initials: HA
authors.lastname: Hou
authors.affiliation: Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: G
authors.initials: G
authors.lastname: Malnassy
authors.affiliation: Division of Hematology, Oncology and Stem Cell Transplantation, Department of Internal Medicine, University of Freiburg Medical Center, Freiburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Ma
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: L-W
authors.initials: LW
authors.lastname: Ding
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: W
authors.initials: W
authors.lastname: Chien
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Ikezoe
authors.affiliation: Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lill
authors.affiliation: Paediatric Haematology-Oncology Department and 'Tettamanti' Research Centre, Milano-Bicocca University, 'Fondazione MBBM', San Gerardo Hospital, Monza, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Biondi
authors.affiliation: Department of Medicine, University of Chicago Comprehensive Cancer Center, Chicago, IL, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Larson
authors.affiliation: Department of Internal Medicine, Section on Hematology and Oncology, Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Powell
authors.affiliation: Division of Hematology, Oncology and Stem Cell Transplantation, Department of Internal Medicine, University of Freiburg Medical Center, Freiburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Lübbert
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.|Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.|Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), The National University Health System (NUHS), Singapore, Singapore.
authors.forename: W J
authors.initials: WJ
authors.lastname: Chng
authors.affiliation: Department of Internal Medicine, National Taiwan University, Medical College and Hospital, Taipei, Taiwan.
authors.forename: H-F
authors.initials: HF
authors.lastname: Tien
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Heuser
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Ganser
authors.affiliation: Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.|Division of Hematology and Bone Marrow Transplantation, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: M
authors.initials: M
authors.lastname: Koren-Michowitz
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: H M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Nowak
authors.affiliation: Department of Hematology and Oncology, University Hospital Mannheim, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany.
authors.forename: W-K
authors.initials: WK
authors.lastname: Hofmann
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: H
authors.initials: H
authors.lastname: Yang
authors.affiliation: Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: W
authors.initials: W
authors.lastname: Stock
authors.affiliation: Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: A
authors.initials: A
authors.lastname: Ghavamzadeh
authors.affiliation: Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: K
authors.initials: K
authors.lastname: Alimoghaddam
authors.affiliation: Munich Leukemia Laboratory (MLL), Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Haferlach
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: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.
authors.forename: L-Y
authors.initials: LY
authors.lastname: Shih
authors.affiliation: Department of Haematology, Christian Medical College, Vellore, India.
authors.forename: V
authors.initials: V
authors.lastname: Mathews
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.|Cedars-Sinai Medical Center, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, CA, USA.|Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), The National University Health System (NUHS), Singapore, Singapore.
authors.forename: H P
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D002454:Cell Differentiation; D004252:DNA Mutational Analysis / Q000379:methods*; D004268:DNA-Binding Proteins / Q000235:genetics; D059472:Exome / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D012008:Recurrence; D014157:Transcription Factors / Q000235:genetics
chemical_list: C112476:ARID1A protein, human; C497837:ARID1B protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors