title: Identification and molecular characterization of recurrent genomic deletions on 7p12 in the IKZF1 gene in a large cohort of BCR-ABL1-positive acute lymphoblastic leukemia patients: on behalf of Gruppo Italiano Malattie Ematologiche dell'Adulto Acute Leukemia Working Party (GIMEMA AL WP).
abstract: The BCR-ABL1 fusion gene defines the subgroup of acute lymphoblastic leukemia (ALL) with the worst clinical prognosis. To identify oncogenic lesions that combine with BCR-ABL1 to cause ALL, we used Affymetrix Genome-Wide Human SNP arrays (250K NspI and SNP 6.0), fluorescence in situ hybridization, and genomic polymerase chain reaction to study 106 cases of adult BCR-ABL1-positive ALL. The most frequent somatic copy number alteration was a focal deletion on 7p12 of IKZF1, which encodes the transcription factor Ikaros and was identified in 80 (75%) of 106 patients. Different patterns of deletions occurred, but the most frequent were those characterized by a loss of exons 4 through 7 (Delta4-7) and by removal of exons 2 through 7 (Delta2-7). A variable number of nucleotides (patient specific) were inserted at the conjunction and maintained with fidelity at the time of relapse. The extent of the Delta4-7 deletion correlated with the expression of a dominant-negative isoform with cytoplasmic localization and oncogenic activity, whereas the Delta2-7 deletion resulted in a transcript lacking the translation start site. The IKZF1 deletion also was identified in the progression of chronic myeloid leukemia to lymphoid blast crisis (66%) but never in myeloid blast crisis or chronic-phase chronic myeloid leukemia or in patients with acute myeloid leukemia. Known DNA sequences and structural features were mapped along the breakpoint cluster regions, including heptamer recombination signal sequences recognized by RAG enzymes during V(D)J recombination, suggesting that IKZF1 deletions could arise from aberrant RAG-mediated recombination.
authors: Department of Hematology/Oncology L and A Seràgnoli S Orsola Malpighi Hospital, University of Bologna, Bologna, Italy.
authors: Ilaria
authors: I
authors: Iacobucci
authors: Clelia Tiziana
authors: CT
authors: Storlazzi
authors: Daniela
authors: D
authors: Cilloni
authors: Annalisa
authors: A
authors: Lonetti
authors: Emanuela
authors: E
authors: Ottaviani
authors: Simona
authors: S
authors: Soverini
authors: Annalisa
authors: A
authors: Astolfi
authors: Sabina
authors: S
authors: Chiaretti
authors: Antonella
authors: A
authors: Vitale
authors: Francesca
authors: F
authors: Messa
authors: Luciana
authors: L
authors: Impera
authors: Carmen
authors: C
authors: Baldazzi
authors: Pietro
authors: P
authors: D'Addabbo
authors: Cristina
authors: C
authors: Papayannidis
authors: Angelo
authors: A
authors: Lonoce
authors: Sabrina
authors: S
authors: Colarossi
authors: Marco
authors: M
authors: Vignetti
authors: Pier Paolo
authors: PP
authors: Piccaluga
authors: Stefania
authors: S
authors: Paolini
authors: Domenico
authors: D
authors: Russo
authors: Fabrizio
authors: F
authors: Pane
authors: Giuseppe
authors: G
authors: Saglio
authors: Michele
authors: M
authors: Baccarani
authors: Robin
authors: R
authors: Foà
authors: Giovanni
authors: G
authors: Martinelli
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence / Q000235:genetics*; D001752:Blast Crisis / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics* / Q000378:metabolism; D018387:Codon, Initiator / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D005091:Exons / Q000235:genetics; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics* / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: D018387:Codon, Initiator; C497239:IKZF1 protein, human; D051740:Ikaros Transcription Factor; D016044:Fusion Proteins, bcr-abl