Conflict of interest: Nothing to declare.
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
Article first published online: 29 JUN 2014
© 2014 Wiley Periodicals, Inc.
Pediatric Blood & Cancer
Volume 61, Issue 10, pages 1779–1785, October 2014
How to Cite
Vitanza, N. A., Zaky, W., Blum, R., Meyer, J. A., Wang, J., Bhatla, T., Morrison, D. J., Raetz, E. A. and Carroll, W. L. (2014), 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. Pediatr. Blood Cancer, 61: 1779–1785. doi: 10.1002/pbc.25119
- Issue published online: 19 AUG 2014
- Article first published online: 29 JUN 2014
- Manuscript Accepted: 7 MAY 2014
- Manuscript Received: 8 APR 2014
- NIH. Grant Numbers: R01 CA140729, R21 CA152838-02, CCSG P30CA016087, T32 CA009161
- American Society of Hematology
- St. Baldrick's Foundation
- Ira Sohn Conference Foundation
- acute lymphoblastic leukemia;
- molecular biology of ALL;
- molecular genetics
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].
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.
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.
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.