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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 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 Citation Map 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. Related Collections Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA 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 Iacobucci1, Annalisa Lonetti1, Francesca Messa2, Daniela Cilloni2, Francesca Arruga2, Emanuela Ottaviani1, Stefania Paolini1, Cristina Papayannidis1, Pier Paolo Piccaluga1, Panagiota Giannoulia1, Simona Soverini1, Marilina Amabile1, Angela Poerio1, Giuseppe Saglio2, Fabrizio Pane3, Giorgio Berton4, Anna Baruzzi4, Antonella Vitale5, Sabina Chiaretti5, Giovanni Perini6, Robin Foà5, Michele Baccarani1, and Giovanni Martinelli1 1 Department of Hematology/Oncology, L. and A. Seràgnoli, S. Orsola Malpighi Hospital, University of Bologna, Bologna; 2 Department of Clinical and Biologic Science, University of Turin at Orbassano, Turin; 3 CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples; 4 Department of Pathology, Section of General Pathology, University of Verona, Verona; 5 La Sapienza University, Department of Cellular Biotechnologies and Hematology, Rome; and 6 Department of Biology, University of Bologna, Bologna, Italy 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. We sought to determine whether molecular abnormalities involving the IKZF1 gene were associated with resistance to tyrosine kinase inhibitors (TKIs) in Ph+ acute lymphoblastic leukemia (ALL) patients. Using reverse-transcribed polymerase chain reaction, 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 versus DNA-binding Ik1 or Ik2 isoforms, which showed nuclear localization. There was a strong correlation between nonfunctional Ikaros isoforms and BCR-ABL transcript level. Furthermore, patient-derived leukemia cells expressed oncogenic Ikaros isoforms before TKI treatment, but not during response to TKIs, and predominantly at the time of relapse. In vitro overexpression 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. These results establish a previously unknown link between specific molecular defects that involve alternative splicing of the IKZF1 gene and the resistance to TKIs in Ph+ ALL patients. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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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