Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome

Matthew T Witkowski, Yifang Hu, Kathryn G Roberts, Judith M. Boer, Mark D McKenzie, Grace Jie Liu, Oliver D. Le Grice, Cedric Tremblay, Margherita Ghisi, Tracy A Willson, Martin A. Horstmann, Ioannis Aifantis, Luisa Cimmino, Seth Frietze, Monique L. den Boer, Charles G Mullighan, Gordon K Smyth, Ross A Dickins

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12 Citations (Scopus)

Abstract

Genetic alterations disrupting the transcription factor IKZF1 (encoding IKAROS) are associated with poor outcome in B lineage acute lymphoblastic leukemia (B-ALL) and occur in >70% of the high-risk BCR-ABL1+ (Ph+) and Ph-like disease subtypes. To examine IKAROS function in this context, we have developed novel mouse models allowing reversible RNAi-based control of Ikaros expression in established B-ALL in vivo. Notably, leukemias driven by combined BCR-ABL1 expression and Ikaros suppression rapidly regress when endogenous Ikaros is restored, causing sustained disease remission or ablation. Comparison of transcriptional profiles accompanying dynamic Ikaros perturbation in murine B-ALL in vivo with two independent human B-ALL cohorts identified nine evolutionarily conserved IKAROS-repressed genes. Notably, high expression of six of these genes is associated with inferior event-free survival in both patient cohorts. Among them are EMP1, which was recently implicated in B-ALL proliferation and prednisolone resistance, and the novel target CTNND1, encoding P120-catenin. We demonstrate that elevated Ctnnd1 expression contributes to maintenance of murine B-ALL cells with compromised Ikaros function. These results suggest that IKZF1 alterations in B-ALL leads to induction of multiple genes associated with proliferation and treatment resistance, identifying potential new therapeutic targets for high-risk disease.

Original languageEnglish
Pages (from-to)773-791
Number of pages19
JournalJournal of Experimental Medicine
Volume214
Issue number3
DOIs
Publication statusPublished - 6 Mar 2017

Cite this

Witkowski, M. T., Hu, Y., Roberts, K. G., Boer, J. M., McKenzie, M. D., Liu, G. J., Le Grice, O. D., Tremblay, C., Ghisi, M., Willson, T. A., Horstmann, M. A., Aifantis, I., Cimmino, L., Frietze, S., den Boer, M. L., Mullighan, C. G., Smyth, G. K., & Dickins, R. A. (2017). Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome. Journal of Experimental Medicine, 214(3), 773-791. https://doi.org/10.1084/jem.20160048