title: Mutational spectrum of adult T-ALL.
abstract: Novel target discovery is warranted to improve treatment in adult T-cell acute lymphoblastic leukemia (T-ALL) patients. We provide a comprehensive study on mutations to enhance the understanding of therapeutic targets and studied 81 adult T-ALL patients. NOTCH1 exhibitedthe highest mutation rate (53%). Mutation frequencies of FBXW7 (10%), WT1 (10%), JAK3 (12%), PHF6 (11%), and BCL11B (10%) were in line with previous reports. We identified recurrent alterations in transcription factors DNM2, and RELN, the WNT pathway associated cadherin FAT1, and in epigenetic regulators (MLL2, EZH2). Interestingly, we discovered novel recurrent mutations in the DNA repair complex member HERC1, in NOTCH2, and in the splicing factor ZRSR2. A frequently affected pathway was the JAK/STAT pathway (18%) and a significant proportion of T-ALL patients harboured mutations in epigenetic regulators (33%), both predominantly found in the unfavourable subgroup of early T-ALL. Importantly, adult T-ALL patients not only showed a highly heterogeneous mutational spectrum, but also variable subclonal allele frequencies implicated in therapy resistance and evolution of relapse. In conclusion, we provide novel insights in genetic alterations of signalling pathways (e.g. druggable by γ-secretase inhibitors, JAK inhibitors or EZH2 inhibitors), present in over 80% of all adult T-ALL patients, that could guide novel therapeutic approaches.
authors.affiliation: Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, Department of Hematology and Oncology, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Neumann
authors.affiliation: Clinical Cooperative Group 'Leukemia', Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.|Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Vosberg
authors.affiliation: Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, Department of Hematology and Oncology, Berlin, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Schlee
authors.affiliation: Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, Department of Hematology and Oncology, Berlin, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Heesch
authors.affiliation: Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, Department of Hematology and Oncology, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schwartz
authors.affiliation: Goethe University Hospital, Department of Medicine II, Hematology/Oncology, Frankfurt/M., Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Gökbuget
authors.affiliation: Goethe University Hospital, Department of Medicine II, Hematology/Oncology, Frankfurt/M., Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Hoelzer
authors.affiliation: Laboratory for Functional Genome Analysis, Gene-Center, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Graf
authors.affiliation: Laboratory for Functional Genome Analysis, Gene-Center, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Krebs
authors.affiliation: Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, Department of Hematology and Oncology, Berlin, Germany.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bartram
authors.affiliation: Laboratory for Functional Genome Analysis, Gene-Center, Ludwig-Maximilians-Universität (LMU), Munich, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Blum
authors.affiliation: University Hospital Kiel, Department of Hematology, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Brüggemann
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hecht
authors.affiliation: Clinical Cooperative Group 'Leukemia', Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.|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: Clinical Cooperative Group 'Leukemia', Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany.|Department of Internal Medicine 3, Ludwig-Maximilians-Universität (LMU), Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: Philipp A
authors.initials: PA
authors.lastname: Greif
authors.affiliation: Charité, Universitätsmedizin Berlin, Campus Benjamin Franklin, Department of Hematology and Oncology, Berlin, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Claudia D
authors.initials: CD
authors.lastname: Baldus
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D057285:Precision Medicine; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000628:therapy; D011237:Predictive Value of Tests; D012008:Recurrence; D000091042:Reelin Protein; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D000091042:Reelin Protein; C000717127:RELN protein, human