title: Targeted sequencing identifies associations between IL7R-JAK mutations and epigenetic modulators in T-cell acute lymphoblastic leukemia.
abstract: T-cell acute lymphoblastic leukemia is caused by the accumulation of multiple oncogenic lesions, including chromosomal rearrangements and mutations. To determine the frequency and co-occurrence of mutations in T-cell acute lymphoblastic leukemia, we performed targeted re-sequencing of 115 genes across 155 diagnostic samples (44 adult and 111 childhood cases). NOTCH1 and CDKN2A/B were mutated/deleted in more than half of the cases, while an additional 37 genes were mutated/deleted in 4% to 20% of cases. We found that IL7R-JAK pathway genes were mutated in 27.7% of cases, with JAK3 mutations being the most frequent event in this group. Copy number variations were also detected, including deletions of CREBBP or CTCF and duplication of MYB. FLT3 mutations were rare, but a novel extracellular mutation in FLT3 was detected and confirmed to be transforming. Furthermore, we identified complex patterns of pairwise associations, including a significant association between mutations in IL7R-JAK genes and epigenetic regulators (WT1, PRC2, PHF6). Our analyses showed that IL7R-JAK genetic lesions did not confer adverse prognosis in T-cell acute lymphoblastic leukemia cases enrolled in the UK ALL2003 trial. Overall, these results identify interconnections between the T-cell acute lymphoblastic leukemia genome and disease biology, and suggest a potential clinical application for JAK inhibitors in a significant proportion of patients with T-cell acute lymphoblastic leukemia.
authors.affiliation: Center for Human Genetics, KU Leuven, Belgium Center for the Biology of Disease, VIB, Leuven, Belgium.
authors.forename: Carmen
authors.initials: C
authors.lastname: Vicente
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Schwab
authors.affiliation: Center for Human Genetics, KU Leuven, Belgium Center for the Biology of Disease, VIB, Leuven, Belgium.
authors.forename: Michaël
authors.initials: M
authors.lastname: Broux
authors.affiliation: Center for Human Genetics, KU Leuven, Belgium Center for the Biology of Disease, VIB, Leuven, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Geerdens
authors.affiliation: Center for Human Genetics, KU Leuven, Belgium Center for the Biology of Disease, VIB, Leuven, Belgium.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Degryse
authors.affiliation: Center for Human Genetics, KU Leuven, Belgium Center for the Biology of Disease, VIB, Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Demeyer
authors.affiliation: Center for Human Genetics, KU Leuven, Belgium Center for the Biology of Disease, VIB, Leuven, Belgium.
authors.forename: Idoya
authors.initials: I
authors.lastname: Lahortiga
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Alannah
authors.initials: A
authors.lastname: Elliott
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Chilton
authors.affiliation: Hematology Unit, University of Perugia, Polo Unico S.M. Misericordia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: La Starza
authors.affiliation: Hematology Unit, University of Perugia, Polo Unico S.M. Misericordia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mecucci
authors.affiliation: Center for Human Genetics, KU Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.affiliation: Department of Haematology, Great Ormond Street Hospital, London, UK.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Goulden
authors.affiliation: Department of Haematology, Sheffield Children's Hospital, Sheffield, UK.
authors.forename: Ajay
authors.initials: A
authors.lastname: Vora
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Moorman
authors.affiliation: U944 INSERM and Hematology Laboratory, St-Louis Hospital, APHP, Hematology University Institute, University Paris-Diderot, Paris, France.
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.affiliation: Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK jan.cools@cme.vib-kuleuven.be christine.harrison@newcastle.ac.uk emmanuelle.clappier@sls.aphp.fr.
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Harrison
authors.affiliation: U944 INSERM and Hematology Laboratory, St-Louis Hospital, APHP, Hematology University Institute, University Paris-Diderot, Paris, France jan.cools@cme.vib-kuleuven.be christine.harrison@newcastle.ac.uk emmanuelle.clappier@sls.aphp.fr.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Clappier
authors.affiliation: Center for Human Genetics, KU Leuven, Belgium Center for the Biology of Disease, VIB, Leuven, Belgium jan.cools@cme.vib-kuleuven.be christine.harrison@newcastle.ac.uk emmanuelle.clappier@sls.aphp.fr.
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
mesh_terms: D000328:Adult; D002648:Child; D060965:Clonal Evolution / Q000235:genetics; D056915:DNA Copy Number Variations; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D056726:Genetic Association Studies; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D053612:Janus Kinases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D020395:Receptors, Interleukin-7 / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction
chemical_list: D020395:Receptors, Interleukin-7; D053612:Janus Kinases