title: Pediatric T-cell lymphoblastic leukemia evolves into relapse by clonal selection, acquisition of mutations and promoter hypomethylation.
abstract: Relapsed precursor T-cell acute lymphoblastic leukemia is characterized by resistance against chemotherapy and is frequently fatal. We aimed at understanding the molecular mechanisms resulting in relapse of T-cell acute lymphoblastic leukemia and analyzed 13 patients at first diagnosis, remission and relapse by whole exome sequencing, targeted ultra-deep sequencing, multiplex ligation dependent probe amplification and DNA methylation array. Compared to primary T-cell acute lymphoblastic leukemia, in relapse the number of single nucleotide variants and small insertions and deletions approximately doubled from 11.5 to 26. Targeted ultra-deep sequencing sensitively detected subclones that were selected for in relapse. The mutational pattern defined two types of relapses. While both are characterized by selection of subclones and acquisition of novel mutations, 'type 1' relapse derives from the primary leukemia whereas 'type 2' relapse originates from a common pre-leukemic ancestor. Relapse-specific changes included activation of the nucleotidase NT5C2 resulting in resistance to chemotherapy and mutations of epigenetic modulators, exemplified by SUZ12, WHSC1 and SMARCA4. While mutations present in primary leukemia and in relapse were enriched for known drivers of leukemia, relapse-specific changes revealed an association with general cancer-promoting mechanisms. This study thus identifies mechanisms that drive progression of pediatric T-cell acute lymphoblastic leukemia to relapse and may explain the characteristic treatment resistance of this condition.
authors: Department of Pediatric Oncology, Hematology and Immunology, Children's Hospital, University of Heidelberg, Germany Molecular Medicine Partnership Unit, EMBL-University of Heidelberg, Germany German Cancer Consortium (DKTK), Heidelberg, Germany.
authors: Joachim B
authors: JB
authors: Kunz
authors: Molecular Medicine Partnership Unit, EMBL-University of Heidelberg, Germany European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany European Molecular Biology Laboratory (EMBL), Genomics Core Facility, Heidelberg, Germany.
authors: Tobias
authors: T
authors: Rausch
authors: Department of Pediatric Oncology, Hematology and Immunology, Children's Hospital, University of Heidelberg, Germany Molecular Medicine Partnership Unit, EMBL-University of Heidelberg, Germany German Cancer Consortium (DKTK), Heidelberg, Germany.
authors: Obul R
authors: OR
authors: Bandapalli
authors: Department of Pediatric Oncology, Hematology and Immunology, Children's Hospital, University of Heidelberg, Germany Molecular Medicine Partnership Unit, EMBL-University of Heidelberg, Germany.
authors: Juliane
authors: J
authors: Eilers
authors: Department of Pediatric Oncology, Hematology and Immunology, Children's Hospital, University of Heidelberg, Germany Molecular Medicine Partnership Unit, EMBL-University of Heidelberg, Germany.
authors: Paulina
authors: P
authors: Pechanska
authors: Department of Pediatric Oncology, Hematology and Immunology, Children's Hospital, University of Heidelberg, Germany Molecular Medicine Partnership Unit, EMBL-University of Heidelberg, Germany.
authors: Stephanie
authors: S
authors: Schuessele
authors: Division of Epigenomics and Cancer Risk Factors, The German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Yassen
authors: Y
authors: Assenov
authors: Molecular Medicine Partnership Unit, EMBL-University of Heidelberg, Germany European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
authors: Adrian M
authors: AM
authors: Stütz
authors: Department of Pediatric Oncology/Hematology, Charité - Universitätsmedizin Berlin, Germany.
authors: Renate
authors: R
authors: Kirschner-Schwabe
authors: Department of Pediatric Oncology/Hematology, Charité - Universitätsmedizin Berlin, Germany German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors: Jana
authors: J
authors: Hof
authors: Department of Pediatric Oncology/Hematology, Charité - Universitätsmedizin Berlin, Germany.
authors: Cornelia
authors: C
authors: Eckert
authors: Department of Pediatric Oncology/Hematology, Charité - Universitätsmedizin Berlin, Germany.
authors: Arend
authors: A
authors: von Stackelberg
authors: Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
authors: Martin
authors: M
authors: Schrappe
authors: Department of Pediatric Hematology/Oncology, Medical School Hannover, Germany.
authors: Martin
authors: M
authors: Stanulla
authors: Department of Human Genetics, University of Heidelberg, Germany.
authors: Rolf
authors: R
authors: Koehler
authors: Molecular Oncology, Felsenstein Medical Research Center and Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
authors: Smadar
authors: S
authors: Avigad
authors: Molecular Oncology, Felsenstein Medical Research Center and Pediatric Hematology Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
authors: Sarah
authors: S
authors: Elitzur
authors: Children's Hospital, University Hospital Tübingen, Germany.
authors: Rupert
authors: R
authors: Handgretinger
authors: European Molecular Biology Laboratory (EMBL), Genomics Core Facility, Heidelberg, Germany.
authors: Vladimir
authors: V
authors: Benes
authors: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany.
authors: Joachim
authors: J
authors: Weischenfeldt
authors: Molecular Medicine Partnership Unit, EMBL-University of Heidelberg, Germany European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany Martina.Muckenthaler@med.uni-heidelberg.de Andreas.Kulozik@med.uni-heidelberg.de jan.korbel@embl-heidelberg.de.
authors: Jan O
authors: JO
authors: Korbel
authors: Department of Pediatric Oncology, Hematology and Immunology, Children's Hospital, University of Heidelberg, Germany Molecular Medicine Partnership Unit, EMBL-University of Heidelberg, Germany Martina.Muckenthaler@med.uni-heidelberg.de Andreas.Kulozik@med.uni-heidelberg.de jan.korbel@embl-heidelberg.de.
authors: Martina U
authors: MU
authors: Muckenthaler
authors: Department of Pediatric Oncology, Hematology and Immunology, Children's Hospital, University of Heidelberg, Germany Molecular Medicine Partnership Unit, EMBL-University of Heidelberg, Germany German Cancer Consortium (DKTK), Heidelberg, Germany Martina.Muckenthaler@med.uni-heidelberg.de Andreas.Kulozik@med.uni-heidelberg.de jan.korbel@embl-heidelberg.de.
authors: Andreas E
authors: AE
authors: Kulozik
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic
chemical_list: D004273:DNA, Neoplasm