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Blood, 1 November 2008, Vol. 112, No. 9, pp. 3847-3855. Prepublished online as a Blood First Edition Paper on July 23, 2008; DOI 10.1182/blood-2007-09-112631. This Article Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-09-112631v1 112/9/3847    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Iacobucci, I. Articles by Martinelli, G. Search for Related Content PubMed PubMed Citation Articles by Iacobucci, I. Articles by Martinelli, G. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 17, 2007 Accepted June 7, 2008 Expression of spliced oncogenic Ikaros isoforms in Philadelphia-positive acute lymphoblastic leukemia patients treated with tyrosine kinase inhibitors: implications for a new mechanism of resistance Ilaria Iacobucci, Annalisa Lonetti, Francesca Messa, Daniela Cilloni, Francesca Arruga, Emanuela Ottaviani, Stefania Paolini, Cristina Papayannidis, Pier Paolo Piccaluga, Panagiota Giannoulia, Simona Soverini, Marilina Amabile, Angela Poerio, Giuseppe Saglio, Fabrizio Pane, Giorgio Berton, Anna Baruzzi, Antonella Vitale, Sabina Chiaretti, Giovanni Perini, Robin Foa, Michele Baccarani, and Giovanni Martinelli* Department of Hematology/Oncology “L. and A. Seragnoli”, S.Orsola Malpighi Hospital, University of Bologna, Bologna, Italy Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy CEINGE Biotecnologie Avanzate and Department of Biochemistry, University of Naples Federico II, Naples, Italy Department of Pathology, Section of General Pathology, University of Verona, Verona, Italy “La Sapienza” University, Department of Cellular Biotechnologies and Hematology, Rome, Italy Department of Biology, University of Bologna, Bologna, Italy * Corresponding author; email: giovanni.martinelli2{at}unibo.it. Rationale: The zinc-finger transcription factor Ikaros plays an important role in the control of differentiation and proliferation of all lymphoid lineages. The expression of short isoforms lacking DNA-binding motifs alters the differentiation capacities of hematopoietic progenitors, arresting lineage commitment. Objectives: We sought to determine whether molecular abnormalities involving the IKZF1 gene were associated with resistance to tyrosine kinase inhibitors (TKIs) in Ph+ ALL patients. Findings: Using RT-PCR, cloning and nucleotide sequencing, only the non-DNA-binding Ik6 isoform was detected in 49% of Ph+ ALL patients. Ik6 was predominantly localized to the cytoplasm compared to DNA-binding Ik1 or Ik2 isoforms, which showed nuclear localization. There was a strong correlation between non-functional Ikaros isoforms and BCR-ABL transcript level. Furthermore, patient-derived leukemia cells expressed oncogenic Ikaros isoforms prior to TKI treatment, but not during response to TKIs, and predominantly at the time of relapse. In vitro over-expression of Ik6 strongly increased DNA synthesis and inhibited apoptosis in TKI sensitive cells. Genomic sequence and computational analyses of exon splice junction regions of IKZF1 in Ph+ ALL patients predicted several mutations that may alter alternative splicing. Conclusions: These results establish a previously unknown link between specific molecular defects that involve alternative splicing of the IKZF1 gene and the resistance to imatinib and dasatinib in Ph+ ALL patients. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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. [Abstract] [Full Text] [PDF] I. Iacobucci, C. T. Storlazzi, D. Cilloni, A. Lonetti, E. Ottaviani, S. Soverini, A. Astolfi, S. Chiaretti, A. Vitale, F. Messa, et al. 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) Blood, September 3, 2009; 114(10): 2159 - 2167. [Abstract] [Full Text] [PDF] D. Trageser, I. Iacobucci, R. Nahar, C. Duy, G. von Levetzow, L. Klemm, E. Park, W. Schuh, T. Gruber, S. Herzog, et al. Pre-B cell receptor-mediated cell cycle arrest in Philadelphia chromosome-positive acute lymphoblastic leukemia requires IKAROS function J. Exp. Med., August 3, 2009; 206(8): 1739 - 1753. [Abstract] [Full Text] [PDF] K. Georgopoulos Acute Lymphoblastic Leukemia -- On the Wings of IKAROS N. Engl. J. Med., January 29, 2009; 360(5): 524 - 526. [Full Text] [PDF] I. Iacobucci, A. Lonetti, D. Cilloni, F. Messa, A. Ferrari, R. Zuntini, S. Ferrari, E. Ottaviani, F. Arruga, S. Paolini, et al. Identification of different Ikaros cDNA transcripts in Philadelphia-positive adult acute lymphoblastic leukemia by a high-throughput capillary electrophoresis sizing method Haematologica, December 1, 2008; 93(12): 1814 - 1821. [Abstract] [Full Text] [PDF]

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