title: Deletions of the long arm of chromosome 5 define subgroups of T-cell acute lymphoblastic leukemia.
abstract: Recurrent deletions of the long arm of chromosome 5 were detected in 23/200 cases of T-cell acute lymphoblastic leukemia. Genomic studies identified two types of deletions: interstitial and terminal. Interstitial 5q deletions, found in five cases, were present in both adults and children with a female predominance (chi-square, P=0.012). Interestingly, these cases resembled immature/early T-cell precursor acute lymphoblastic leukemia showing significant down-regulation of five out of the ten top differentially expressed genes in this leukemia group, including TCF7 which maps within the 5q31 common deleted region. Mutations of genes known to be associated with immature/early T-cell precursor acute lymphoblastic leukemia, i.e. WT1, ETV6, JAK1, JAK3, and RUNX1, were present, while CDKN2A/B deletions/mutations were never detected. All patients had relapsed/resistant disease and blasts showed an early differentiation arrest with expression of myeloid markers. Terminal 5q deletions, found in 18 of patients, were more prevalent in adults (chi-square, P=0.010) and defined a subgroup of HOXA-positive T-cell acute lymphoblastic leukemia characterized by 130 up- and 197 down-regulated genes. Down-regulated genes included TRIM41, ZFP62, MAPK9, MGAT1, and CNOT6, all mapping within the 1.4 Mb common deleted region at 5q35.3. Of interest, besides CNOT6 down-regulation, these cases also showed low BTG1 expression and a high incidence of CNOT3 mutations, suggesting that the CCR4-NOT complex plays a crucial role in the pathogenesis of HOXA-positive T-cell acute lymphoblastic leukemia with terminal 5q deletions. In conclusion, interstitial and terminal 5q deletions are recurrent genomic losses identifying distinct subtypes of T-cell acute lymphoblastic leukemia.
authors.affiliation: Molecular Medicine Laboratory, Center for Hemato-Oncology Research, University of Perugia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: La Starza
authors.affiliation: Molecular Medicine Laboratory, Center for Hemato-Oncology Research, University of Perugia, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Barba
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: Molecular Medicine Laboratory, Center for Hemato-Oncology Research, University of Perugia, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Pierini
authors.affiliation: Molecular Medicine Laboratory, Center for Hemato-Oncology Research, University of Perugia, Italy.
authors.forename: Danika
authors.initials: D
authors.lastname: Di Giacomo
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Gianfelici
authors.affiliation: Leukaemia Research Cytogenetic Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Schwab
authors.affiliation: Molecular Medicine Laboratory, Center for Hemato-Oncology Research, University of Perugia, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Matteucci
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: Center for Human Genetics, KU Leuven, Belgium Center for the Biology of Disease, VIB, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University, Rome, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Messina
authors.affiliation: Molecular Medicine Laboratory, Center for Hemato-Oncology Research, University of Perugia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Crescenzi
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University, Rome, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Chiaretti
authors.affiliation: Hematology, Department of Cellular Biotechnologies and Hematology, "Sapienza" University, Rome, Italy.
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
authors.affiliation: Pediatric Hemato-Oncology, Department of Pediatrics "Salus Pueri", University of Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Basso
authors.affiliation: Leukaemia Research Cytogenetic Group, Northern Institute for Cancer Research, Newcastle University, Newcastle-upon-Tyne, UK.
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Harrison
authors.affiliation: Molecular Medicine Laboratory, Center for Hemato-Oncology Research, University of Perugia, Italy cristina.mecucci@unipg.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mecucci
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers; D002648:Child; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D015415:Biomarkers; D018398:Homeodomain Proteins; C088144:HoxA protein