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Ikaros deletions in BCR–ABL-negative childhood acute lymphoblastic leukemia are associated with a distinct gene expression signature but do not result in intrinsic chemoresistance

Authors

  • Nicholas A. Vitanza MD,

    1. Department of Pediatric Hematology/Oncology, Laura and Isaac Perlmutter Cancer Center at New York University Langone Medical Center, New York, New York
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  • Wafik Zaky MD,

    1. Department of Pediatric Patient Care, University of Texas MD Anderson Cancer Center, Houston, Texas
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  • Roy Blum PhD,

    1. Department of Pathology, New York University School of Medicine, New York, New York
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  • Julia A. Meyer PhD,

    1. Department of Pathology, New York University School of Medicine, New York, New York
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  • Jinhua Wang PhD,

    1. Department of Pediatric Hematology/Oncology, Laura and Isaac Perlmutter Cancer Center at New York University Langone Medical Center, New York, New York
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  • Teena Bhatla MD,

    1. Department of Pediatric Hematology/Oncology, Laura and Isaac Perlmutter Cancer Center at New York University Langone Medical Center, New York, New York
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  • Debra J. Morrison PhD,

    1. Department of Pediatric Hematology/Oncology, Laura and Isaac Perlmutter Cancer Center at New York University Langone Medical Center, New York, New York
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  • Elizabeth A. Raetz MD,

    1. Department of Pediatrics, Huntsman Cancer Institute and Primary Children's Hospital, University of Utah, Salt Lake City, Utah
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  • William L. Carroll MD

    Corresponding author
    1. Department of Pediatric Hematology/Oncology, Laura and Isaac Perlmutter Cancer Center at New York University Langone Medical Center, New York, New York
    • Correspondence to: William L. Carroll, NYU Cancer Institute, Smilow 1201, 522 First Avenue, New York, NY 10016.

      E-mail: william.carroll@nyumc.org

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  • Conflict of interest: Nothing to declare.

Abstract

Background

Ikaros, the product of IKZF1, is a regulator of lymphoid development and polymorphisms in the gene have been associated with the acute lymphoblastic leukemia (ALL). Additionally, IKZF1 deletions and mutations identify high-risk biological subsets of childhood ALL [Georgopoulos et al. Cell 1995;83(2):289–299; Mullighan et al. N Engl J Md 2009;360(5):470–480].

Procedures

To discover the underlying pathways modulated by Ikaros we performed gene expression and gene ontology analysis in IKZF1 deleted primary B-ALL pediatric patient samples. To validate downstream targets we performed qPCR on individual patient samples. We also created IKZF1 knockdown B-ALL cell lines with over 50% reduction of Ikaros, mimicking haplosufficient Ikaros deletions, and again performed qPCR to investigate the downstream targets. Finally, to understand the association of Ikaros deletion with a poor prognosis we challenged our IKZF1 knockdown cell lines with chemotherapy and compared responses to IKZF1 wild-type controls.

Results

We report a specific gene expression signature of 735 up-regulated and 473 down-regulated genes in IKZF1 deleted primary B-ALL pediatric patient samples. Gene ontology studies revealed an up-regulation of genes associated with cell adhesion, cytoskeletal regulation, and motility in IKZF deleted patient samples. Validated up-regulated target genes in IKZF1 deleted patient samples included CTNND1 and PVRL2 (P = 0.0003 and P = 0.001), and RAB3IP and SPIB (P = 0.005 and P = 0.032) were down-regulated. In further studies in IKZF1 knockdown cell lines, apoptosis assays showed no significant chemoresistance.

Conclusion

IKZF1 knockdown alone does not impart intrinsic chemotherapy resistance suggesting that the association with a poor prognosis may be due to additional lesions, microenvironmental interactions with the bone marrow niche, or other factors. Pediatr Blood Cancer 2014; 61:1779–1785. © 2014 Wiley Periodicals, Inc.

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