title: Acute myeloid leukemia with del(9q) is characterized by frequent mutations of NPM1, DNMT3A, WT1 and low expression of TLE4.
abstract: Deletions of the long arm of chromosome 9 [del(9q)] are a rare but recurring aberration in acute myeloid leukemia (AML). Del(9q) can be found as the sole abnormality or in combination with other cytogenetic aberrations such as t(8;21) and t(15;17). TLE1 and TLE4 were identified to be critical genes contained in the 9q region. We performed whole exome sequencing of 5 patients with del(9q) as the sole abnormality followed by targeted amplicon sequencing of 137 genes of 26 patients with del(9q) as sole or combined with other aberrations. We detected frequent mutations in NPM1 (10/26; 38%), DNMT3A (8/26; 31%), and WT1 (8/26; 31%) but only few FLT3-ITDs (2/26; 8%). All mutations affecting NPM1 and DNMT3A were exclusively identified in patients with del(9q) as the sole abnormality and were significantly more frequent compared to 111 patients classified as intermediate-II according to the European LeukemiaNet (10/14, 71% vs. 22/111, 20%; P < 0.001, 8/14, 57% vs. 26/111, 23%; P = 0.02). Furthermore, we identified DNMT3B to be rarely but recurrently targeted by truncating mutations in AML. Gene expression analysis of 13 patients with del(9q) and 454 patients with normal karyotype or various cytogenetic aberrations showed significant down regulation of TLE4 in patients with del(9q) (P = 0.02). Interestingly, downregulation of TLE4 was not limited to AML with del(9q), potentially representing a common mechanism in AML pathogenesis. Our comprehensive genetic analysis of the del(9q) subgroup reveals a unique mutational profile with the frequency of DNMT3A mutations in the del(9q) only subset being the highest reported so far in AML, indicating oncogenic cooperativity. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU) München, München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Center Munich for Environmental Health, München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Tobias
authors.identifier: 0000-0002-9615-9432
authors.initials: T
authors.lastname: Herold
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU) München, München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Center Munich for Environmental Health, München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Metzeler
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU) München, München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Center Munich for Environmental Health, München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Vosberg
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU) München, München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Center Munich for Environmental Health, München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Luise
authors.initials: L
authors.lastname: Hartmann
authors.affiliation: Institute for Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität (LMU) München, München, Germany.
authors.forename: Vindi
authors.initials: V
authors.lastname: Jurinovic
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU) München, München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Center Munich for Environmental Health, München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Opatz
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU) München, München, Germany.
authors.forename: Nikola P
authors.initials: NP
authors.lastname: Konstandin
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU) München, München, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU) München, München, Germany.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Zellmeier
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU) München, München, Germany.
authors.forename: Bianka
authors.initials: B
authors.lastname: Ksienzyk
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität (LMU) München, München, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Graf
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität (LMU) München, München, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Krebs
authors.affiliation: Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, Ludwig-Maximilians-Universität (LMU) München, München, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Blum
authors.affiliation: Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Cristina Sauerland
authors.affiliation: Department of Medicine A-Hematology, Oncology and Pneumology, University of Münster, Münster, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Büchner
authors.affiliation: Department of Medicine A-Hematology, Oncology and Pneumology, University of Münster, Münster, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.affiliation: Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine, Campus Virchow, Berlin, Germany.
authors.forename: Bernhard J
authors.initials: BJ
authors.lastname: Wörmann
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|Institute for Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität (LMU) München, München, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Mansmann
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU) München, München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Center Munich for Environmental Health, München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hiddemann
authors.affiliation: Department of Molecular Medicine and Pathology, The University of Auckland, Auckland, New Zealand.
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Bohlander
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU) München, München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Center Munich for Environmental Health, München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Spiekermann
authors.affiliation: Department of Internal Medicine 3, University Hospital Grosshadern, Ludwig-Maximilians-Universität (LMU) München, München, Germany.|Clinical Cooperative Group Leukemia, Helmholtz Center Munich for Environmental Health, München, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Greif
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D015331:Cohort Studies; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D059472:Exome / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics*; D000090243:Nucleophosmin; D011379:Prognosis; D012097:Repressor Proteins / Q000235:genetics*; D015996:Survival Rate; D025721:WT1 Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C000717967:DNMT3A protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; C465817:TLE4 protein, human; D025721:WT1 Proteins; C583751:WT1 protein, human; D000090243:Nucleophosmin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A