title: Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse.
abstract: Acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologic malignancy with a grave prognosis. To identify the mutational spectrum associated with relapse, whole-exome sequencing was performed on 13 matched diagnosis, relapse, and remission trios followed by targeted sequencing of 299 genes in 67 FLT3-ITD patients. The FLT3-ITD genome has an average of 13 mutations per sample, similar to other AML subtypes, which is a low mutation rate compared with that in solid tumors. Recurrent mutations occur in genes related to DNA methylation, chromatin, histone methylation, myeloid transcription factors, signaling, adhesion, cohesin complex, and the spliceosome. Their pattern of mutual exclusivity and cooperation among mutated genes suggests that these genes have a strong biological relationship. In addition, we identified mutations in previously unappreciated genes such as MLL3, NSD1, FAT1, FAT4, and IDH3B. Mutations in 9 genes were observed in the relapse-specific phase. DNMT3A mutations are the most stable mutations, and this DNMT3A-transformed clone can be present even in morphologic complete remissions. Of note, all AML matched trio samples shared at least 1 genomic alteration at diagnosis and relapse, suggesting common ancestral clones. Two types of clonal evolution occur at relapse: either the founder clone recurs or a subclone of the founder clone escapes from induction chemotherapy and expands at relapse by acquiring new mutations. Relapse-specific mutations displayed an increase in transversions. Functional assays demonstrated that both MLL3 and FAT1 exert tumor-suppressor activity in the FLT3-ITD subtype. An inhibitor of XPO1 synergized with standard AML induction chemotherapy to inhibit FLT3-ITD growth. This study clearly shows that FLT3-ITD AML requires additional driver genetic alterations in addition to FLT3-ITD alone.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore;
authors.forename: Manoj
authors.identifier: http://orcid.org/0000-0002-3492-2957
authors.initials: M
authors.lastname: Garg
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Nagata
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore;
authors.forename: Deepika
authors.initials: D
authors.lastname: Kanojia
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore;
authors.forename: Anand
authors.initials: A
authors.lastname: Mayakonda
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Kenichi
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore;
authors.forename: Sreya
authors.initials: S
authors.lastname: Haridas Keloth
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore;
authors.forename: Zhi Jiang
authors.initials: ZJ
authors.lastname: Zang
authors.affiliation: Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan;
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.affiliation: Laboratory of DNA Information Analysis, and.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Laboratory of DNA Information Analysis, and.
authors.forename: Kenichi
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authors.lastname: Chiba
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan;
authors.forename: Hiroko
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authors.lastname: Tanaka
authors.affiliation: Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan;
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore;
authors.forename: Ling-Wen
authors.initials: LW
authors.lastname: Ding
authors.affiliation: Munich Leukemia Laboratory, Munich, Germany;
authors.forename: Tamara
authors.initials: T
authors.lastname: Alpermann
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore;
authors.forename: Qiao-Yang
authors.initials: QY
authors.lastname: Sun
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore;
authors.forename: De-Chen
authors.initials: DC
authors.lastname: Lin
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore;
authors.forename: Wenwen
authors.initials: W
authors.lastname: Chien
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore;
authors.forename: Vikas
authors.initials: V
authors.lastname: Madan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore;
authors.forename: Li-Zhen
authors.initials: LZ
authors.lastname: Liu
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore;
authors.forename: Kar-Tong
authors.initials: KT
authors.lastname: Tan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore;
authors.forename: Abhishek
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authors.lastname: Sampath
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore;
authors.forename: Subhashree
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authors.lastname: Venkatesan
authors.affiliation: Department of Hematology, Nippon Medical School, Tokyo, Japan;
authors.forename: Koiti
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authors.lastname: Inokuchi
authors.affiliation: Department of Hematology, Nippon Medical School, Tokyo, Japan;
authors.forename: Satoshi
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authors.lastname: Wakita
authors.affiliation: Department of Hematology, Nippon Medical School, Tokyo, Japan;
authors.forename: Hiroki
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authors.lastname: Yamaguchi
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore;
authors.forename: Wee Joo
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authors.lastname: Chng
authors.affiliation: Department of Paediatrics, National University Health System, Singapore;
authors.forename: Shirley-Kow Yin
authors.initials: SK
authors.lastname: Kham
authors.affiliation: Department of Paediatrics, National University Health System, Singapore;
authors.forename: Allen Eng-Juh
authors.initials: AE
authors.lastname: Yeoh
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Advanced Diagnosis, Clinical Research Center, Nagoya Medical Center, Nagoya, Japan;
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.affiliation: Department I of Internal Medicine, University of Cologne, Cologne, Germany;
authors.forename: Joanna
authors.initials: J
authors.lastname: Schiller
authors.affiliation: Department I of Internal Medicine, University of Cologne, Cologne, Germany;
authors.forename: Karl-Anton
authors.initials: KA
authors.lastname: Kreuzer
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kornblau
authors.affiliation: Department of Leukemia, MD Anderson Cancer Center, Houston, TX; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX;
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Munich Leukemia Laboratory, Munich, Germany;
authors.forename: Torsten
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authors.lastname: Haferlach
authors.affiliation: Cedars-Sinai Medical Center, Division of Hematology/Oncology, University of California Los Angeles, School of Medicine, Los Angeles, CA;
authors.forename: Michael
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authors.lastname: Lill
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan;
authors.forename: Ming-Chung
authors.initials: MC
authors.lastname: Kuo
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan;
authors.forename: Lee-Yung
authors.initials: LY
authors.lastname: Shih
authors.affiliation: Department of Hematology, Oncology and Tumorimmunology, Charite University School of Medicine, Berlin, Germany; and.
authors.forename: Igor-Wolfgang
authors.initials: IW
authors.lastname: Blau
authors.affiliation: Department of Hematology, Oncology and Tumorimmunology, Charite University School of Medicine, Berlin, Germany; and.
authors.forename: Olga
authors.initials: O
authors.lastname: Blau
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore;
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore; Cedars-Sinai Medical Center, Division of Hematology/Oncology, University of California Los Angeles, School of Medicine, Los Angeles, CA; National University Cancer Institute, National University Hospital, Singapore.
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D059472:Exome; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D008297:Male; D009154:Mutation; D012008:Recurrence; D012189:Retrospective Studies; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D002843:Chromatin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3