title: Combined interphase fluorescence in situ hybridization elucidates the genetic heterogeneity of T-cell acute lymphoblastic leukemia in adults.
abstract: BACKGROUND
  Molecular lesions in T-cell acute lymphoblastic leukemias affect regulators of cell cycle, proliferation, differentiation, survival and apoptosis in multi-step pathogenic pathways. Full genetic characterization is needed to identify events concurring in the development of these leukemias.
  
  
  METHODS
  We designed a combined interphase fluorescence in situ hybridization strategy to study 25 oncogenes/tumor suppressor genes in T-cell acute lymphoblastic leukemias and applied it in 23 adult patients for whom immunophenotyping, karyotyping, molecular studies, and gene expression profiling data were available. The results were confirmed and integrated with those of multiplex-polymerase chain reaction analysis and gene expression profiling in another 129 adults with T-cell acute lymphoblastic leukemias.
  
  
  RESULTS
  The combined hybridization was abnormal in 21/23 patients (91%), and revealed multiple genomic changes in 13 (56%). It found abnormalities known to be associated with T-cell acute lymphoblastic leukemias, i.e. CDKN2A-B/9p21 and GRIK2/6q16 deletions, TCR and TLX3 rearrangements, SIL-TAL1, CALM-AF10, MLL-translocations, del(17)(q12)/NF1 and other cryptic genomic imbalances, i.e. 9q34, 11p, 12p, and 17q11 duplication, del(5)(q35), del(7)(q34), del(9)(q34), del(12)(p13), and del(14)(q11). It revealed new cytogenetic mechanisms for TCRB-driven oncogene activation and C-MYB duplication. In two cases with cryptic del(9)(q34), fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction detected the TAF_INUP214 fusion and gene expression profiling identified a signature characterized by HOXA and NUP214 upregulation and TAF_I, FNBP1, C9orf78, and USP20 down-regulation. Multiplex-polymerase chain reaction analysis and gene expression profiling of 129 further cases found five additional cases of TAF_I-NUP214-positive T-cell acute lymphoblastic leukemia.
  
  
  CONCLUSIONS
  Our combined interphase fluorescence in situ hybridization strategy greatly improved the detection of genetic abnormalities in adult T-cell acute lymphoblastic leukemias. It identified new tumor suppressor genes/oncogenes involved in leukemogenesis and highlighted concurrent involvement of genes. The estimated incidence of TAF_I-NUP214, a new recurrent fusion in adult T-cell acute lymphoblastic leukemias, was 4.6% (7/152).
authors.affiliation: Hematology and Bone Marrow Transplantation Unit, University of Perugia, Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Gorello
authors.forename: Roberta
authors.initials: R
authors.lastname: La Starza
authors.forename: Emanuela
authors.initials: E
authors.lastname: Varasano
authors.forename: Sabina
authors.initials: S
authors.lastname: Chiaretti
authors.forename: Loredana
authors.initials: L
authors.lastname: Elia
authors.forename: Valentina
authors.initials: V
authors.lastname: Pierini
authors.forename: Gianluca
authors.initials: G
authors.lastname: Barba
authors.forename: Lucia
authors.initials: L
authors.lastname: Brandimarte
authors.forename: Barbara
authors.initials: B
authors.lastname: Crescenzi
authors.forename: Antonella
authors.initials: A
authors.lastname: Vitale
authors.forename: Monica
authors.initials: M
authors.lastname: Messina
authors.forename: Sara
authors.initials: S
authors.lastname: Grammatico
authors.forename: Marco
authors.initials: M
authors.lastname: Mancini
authors.forename: Caterina
authors.initials: C
authors.lastname: Matteucci
authors.forename: Antonella
authors.initials: A
authors.lastname: Bardi
authors.forename: Anna
authors.initials: A
authors.lastname: Guarini
authors.forename: Massimo Fabrizio
authors.initials: MF
authors.lastname: Martelli
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
authors.forename: Cristina
authors.initials: C
authors.lastname: Mecucci
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D055028:Comparative Genomic Hybridization; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D018740:Genetic Heterogeneity; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D055815:Young Adult