title: Whole-exome sequencing in adult ETP-ALL reveals a high rate of DNMT3A mutations.
abstract: Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) is a high-risk subgroup of T-lineage ALL characterized by specific stem cell and myeloid features. In adult ETP-ALL, no comprehensive studies on the genetic background have been performed to elucidate molecular lesions of this distinct subgroup. We performed whole-exome sequencing of 5 paired ETP-ALL samples. In addition to mutations in genes known to be involved in leukemogenesis (ETV6, NOTCH1, JAK1, and NF1), we identified novel recurrent mutations in FAT1 (25%), FAT3 (20%), DNM2 (35%), and genes associated with epigenetic regulation (MLL2, BMI1, and DNMT3A). Importantly, we verified the high rate of DNMT3A mutations (16%) in a larger cohort of adult patients with ETP-ALL (10/68). Mutations in epigenetic regulators support clinical trials, including epigenetic-orientated therapies, for this high-risk subgroup. Interestingly, more than 60% of adult patients with ETP-ALL harbor at least a single genetic lesion in DNMT3A, FLT3, or NOTCH1 that may allow use of targeted therapies.
authors.affiliation: Department of Hematology and Oncology, Campus Benjamin Franklin, Charité, University Hospital Berlin, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Neumann
authors.forename: Sandra
authors.initials: S
authors.lastname: Heesch
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schlee
authors.forename: Stefan
authors.initials: S
authors.lastname: Schwartz
authors.forename: Nicola
authors.initials: N
authors.lastname: Gökbuget
authors.forename: Dieter
authors.initials: D
authors.lastname: Hoelzer
authors.forename: Nikola P
authors.initials: NP
authors.lastname: Konstandin
authors.forename: Bianka
authors.initials: B
authors.lastname: Ksienzyk
authors.forename: Sebastian
authors.initials: S
authors.lastname: Vosberg
authors.forename: Alexander
authors.initials: A
authors.lastname: Graf
authors.forename: Stefan
authors.initials: S
authors.lastname: Krebs
authors.forename: Helmut
authors.initials: H
authors.lastname: Blum
authors.forename: Thorsten
authors.initials: T
authors.lastname: Raff
authors.forename: Monika
authors.initials: M
authors.lastname: Brüggemann
authors.forename: Wolf-Karsten
authors.initials: WK
authors.lastname: Hofmann
authors.forename: Jochen
authors.initials: J
authors.lastname: Hecht
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Bohlander
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Greif
authors.forename: Claudia D
authors.initials: CD
authors.lastname: Baldus
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic; D059472:Exome / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D054504:Precursor Cells, T-Lymphoid / Q000473:pathology*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011379:Prognosis; D051881:Receptor, Notch1 / Q000235:genetics; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C000717967:DNMT3A protein, human; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3