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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.
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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.
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I. Iacobucci, A. Lonetti, D. Cilloni, F. Messa, A. Ferrari, R. Zuntini, S. Ferrari, E. Ottaviani, F. Arruga, S. Paolini, et al.
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