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Blood, 3 September 2009, Vol. 114, No. 10, pp. 2159-2167.
Prepublished online as a Blood First Edition Paper on July 9, 2009; DOI 10.1182/blood-2008-08-173963.
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Submitted August 13, 2008
Accepted March 28, 2009
Identification and molecular characterisation of recurrent genomic deletions on 7p12 in the IKZF1 gene in a large cohort of BCR-ABL1-positive acute lymphoblastic leukaemia patients: on behalf of GIMEMA AL WP
Ilaria Iacobucci, Clelia Tiziana Storlazzi, Daniela Cilloni, Annalisa Lonetti, Emanuela Ottaviani, Simona Soverini, Annalisa Astolfi, Sabina Chiaretti, Antonella Vitale, Francesca Messa, Luciana Impera, Carmen Baldazzi, Pietro D'Addabbo, Cristina Papayannidis, Angelo Lonoce, Sabrina Colarossi, Marco Vignetti, Pier Paolo Piccaluga, Stefania Paolini, Domenico Russo, Fabrizio Pane, Giuseppe Saglio, Michele Baccarani, Robin Foa, and Giovanni Martinelli*
Department of Hematology/Oncology "L. and A. Seragnoli", S. Orsola Malpighi Hospital, University of Bologna, Bologna, Italy
Department of Genetics and Microbiology, University of Bari, Bari, Italy
Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy
Pediatric Oncology and Hematology "L. Seragnoli", Bologna, Italy
"La Sapienza" University, Department of Cellular Biotechnologies and Hematology, Rome, Italy
Hematology and Bone Marrow Transplantation Unit, Spedali Civili Hospital, University of Brescia, Brescia, Italy
CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
* Corresponding author; email: giovanni.martinelli2{at}unibo.it.
The BCR-ABL1 fusion gene defines the subgroup of acute lymphoblastic leukaemia (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), FISH and genomic PCR 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 of 106 patients (75%). Different patterns of deletions occurred but the most frequent were those characterised by a loss of exons 4 through 7 ( 4-7), and by removal of exons 2 through 7 (2-7). 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 4-7 deletion correlated with the expression of a dominant-negative isoform with cytoplasmic localisation and oncogenic activity, while the 2-7 deletion resulted in a transcript lacking the translation start site. The IKZF1 deletion was also identified in the progression of chronic myeloid leukaemia (CML) to lymphoid blast crisis (66%), but never in myeloid blast crisis or chronic phase CML, or in acute myeloid leukaemia patients. Known DNA sequence and structural features were mapped along the breakpoint cluster regions including heptamer recombination signal sequences (RSS) recognised by RAG enzymes during V(D)J recombination, suggesting that IKZF1 deletions could arise from aberrant RAG-mediated recombination.
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G. Martinelli, I. Iacobucci, C. T. Storlazzi, M. Vignetti, F. Paoloni, D. Cilloni, S. Soverini, A. Vitale, S. Chiaretti, G. Cimino, et al.
IKZF1 (Ikaros) Deletions in BCR-ABL1-Positive Acute Lymphoblastic Leukemia Are Associated With Short Disease-Free Survival and High Rate of Cumulative Incidence of Relapse: A GIMEMA AL WP Report
J. Clin. Oncol.,
November 1, 2009;
27(31):
5202 - 5207.
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