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Cellular and Molecular Biology

Abstract #1287: IKZF1 (Ikaros) Deletions are a frequent event in BCR-ABL1 Positive Acute Lymphoblastic Leukemia (ALL) and are associated with an impaired B-cell differentiation and poor outcome: A GIMEMA ALL Working Party Report

Ilaria Iacobucci, Annalisa Lonetti, Anna Ferrari, Clelia Tiziana Storlazzi, Emanuela Ottaviani, Sabina Chiaretti, Monica Messina, Daniela Cilloni, Carmen Baldazzi, Cristina Papayannidis, Francesca Messa, Annalisa Astolfi, Luciana Impera, Antonella Vitale, Francesca Arruga, Fabrizio Pane, Pier Paolo Piccaluga, Sabrina Colarossi, Simona Soverini, Marco Vignetti, Stefania Paolini, Giuseppe Saglio, Michele Baccarani, Robin Foà and Giovanni Martinelli
Ilaria Iacobucci
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Annalisa Lonetti
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Anna Ferrari
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Clelia Tiziana Storlazzi
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Emanuela Ottaviani
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Sabina Chiaretti
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Monica Messina
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Daniela Cilloni
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Carmen Baldazzi
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Cristina Papayannidis
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Francesca Messa
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Annalisa Astolfi
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Luciana Impera
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Antonella Vitale
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Francesca Arruga
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Fabrizio Pane
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Pier Paolo Piccaluga
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Sabrina Colarossi
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Simona Soverini
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Marco Vignetti
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Stefania Paolini
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Giuseppe Saglio
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Michele Baccarani
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Robin Foà
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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Giovanni Martinelli
Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Department of Genetics and Microbiology - University of Bari, Bari, Italy; Dept. of Cellular Biotechnologies and Hematology - %93La Sapienza%94 University, Rome, Italy; Department of Clinical and Biological Science, University of Turin at Orbassano, Turin, Italy; Department of Hematology/Oncology Ser%E0gnoli - University of Bologna, Bologna, Italy; Pediatric Oncology and Hematology %93L. Ser%E0gnoli%94, Bologna, Italy; CEINGE Biotecnologie Avanzate and Department of Biochemistry and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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DOI:  Published May 2009
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AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Abstract

By genome-wide analyses of DNA copy number abnormalities in adult BCR-ABL1-positive ALL patients (pts) using single nucleotide polymorphism (SNP) microarrays (Affymetrix 500K and SNP 6.0), we identified a high frequency of genetic alterations of regulators of B lymphoid development (PAX5, EBF1, IKZF1) and cell cycle (CDKN2A, CDKN2B, BTG1). The most frequent somatic copy number alteration was deletion on 7p12 of IKZF1 (68/106 patients, 64%), which encodes the transcription factor Ikaros required for the earliest stages of lymphoid lineage commitment. Here, we characterized and mapped all breakpoints in IKZF1 gene to recognize that two major deletions occur in BCR-ABL1-positive ALL: type A characterized by loss of exons 4-7 (44%) and due to breakpoints occurring in introns 3 and 7; type B characterized by removal of exons 2-7 (19%) and due to a variable pattern of breakpoints in introns 1 and 7. In two pts we had both \#916;2-7 and \#916;4-7 deletions and in one we identified a deletion of all IKZF1 gene and part of GRB10. A variable number of nucleotides (patient-specific) were inserted at the conjunction and maintained with fidelity at the time of relapse. The extent of both deletions correlated with the expression of dominant-negative isoforms with cytoplasmatic localization. The IKZF1 alteration was also identified in B-negative ALL pts (41%) and at the progression of CML to lymphoid blast crisis (66%), but never in myeloid blast crisis CML and chronic phase CML. Known DNA sequences were mapped along the breakpoint cluster regions including heptamer recombination signal sequences recognized by the RAG enzymes during V(D)J recombination and activation-induced cytidine deaminase (AID) consensus motifs (DGYW/WRCH). Gene expression profiling analysis of pts with IKZF1 deletion vs wild-type pts identified a unique signature characterized by a down-regulation of genes involved in pre-B-cell differentiation (e.g. VPREB1, VPREB3, IGLL3, BLK), demonstrating that genomic IKZF1 alterations have a strong impact on trascriptoma and contribute to an impaired B-cell differentiation. Univariate analysis showed that the IKZF1 deletion is a negative prognostic marker influencing the cumulative incidence of relapse (10.1 months for pts with deletion vs 56.1 months for wild-type pts, p=0.0103) and disease-free survival (DFS) (10.1 months vs 32.1 months, respectively, p=0.0229). The negative prognostic impact of the IKZF1 deletion on DFS was also confirmed by multivariate analysis (p=0.0445). In conclusion, deletion of IKZF1 is an important event in the development of BCR-ABL1 B-progenitor ALL which significantly influences clinical outcome. Supported by: European LeukemiaNet, AIL, AIRC, FIRB 2006, Fondazione del Monte di Bologna e Ravenna, Strategico di Ateneo, GIMEMA Onlus.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1287.

Footnotes

  • 100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

  • American Association for Cancer Research
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Cancer Research: 69 (9 Supplement)
May 2009
Volume 69, Issue 9 Supplement
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Abstract #1287: IKZF1 (Ikaros) Deletions are a frequent event in BCR-ABL1 Positive Acute Lymphoblastic Leukemia (ALL) and are associated with an impaired B-cell differentiation and poor outcome: A GIMEMA ALL Working Party Report
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Abstract #1287: IKZF1 (Ikaros) Deletions are a frequent event in BCR-ABL1 Positive Acute Lymphoblastic Leukemia (ALL) and are associated with an impaired B-cell differentiation and poor outcome: A GIMEMA ALL Working Party Report
Ilaria Iacobucci, Annalisa Lonetti, Anna Ferrari, Clelia Tiziana Storlazzi, Emanuela Ottaviani, Sabina Chiaretti, Monica Messina, Daniela Cilloni, Carmen Baldazzi, Cristina Papayannidis, Francesca Messa, Annalisa Astolfi, Luciana Impera, Antonella Vitale, Francesca Arruga, Fabrizio Pane, Pier Paolo Piccaluga, Sabrina Colarossi, Simona Soverini, Marco Vignetti, Stefania Paolini, Giuseppe Saglio, Michele Baccarani, Robin Foà and Giovanni Martinelli
Cancer Res May 1 2009 (69) (9 Supplement) 1287;

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Abstract #1287: IKZF1 (Ikaros) Deletions are a frequent event in BCR-ABL1 Positive Acute Lymphoblastic Leukemia (ALL) and are associated with an impaired B-cell differentiation and poor outcome: A GIMEMA ALL Working Party Report
Ilaria Iacobucci, Annalisa Lonetti, Anna Ferrari, Clelia Tiziana Storlazzi, Emanuela Ottaviani, Sabina Chiaretti, Monica Messina, Daniela Cilloni, Carmen Baldazzi, Cristina Papayannidis, Francesca Messa, Annalisa Astolfi, Luciana Impera, Antonella Vitale, Francesca Arruga, Fabrizio Pane, Pier Paolo Piccaluga, Sabrina Colarossi, Simona Soverini, Marco Vignetti, Stefania Paolini, Giuseppe Saglio, Michele Baccarani, Robin Foà and Giovanni Martinelli
Cancer Res May 1 2009 (69) (9 Supplement) 1287;
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Cancer Research Online ISSN: 1538-7445
Cancer Research Print ISSN: 0008-5472
Journal of Cancer Research ISSN: 0099-7013
American Journal of Cancer ISSN: 0099-7374

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