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

Research output: Contribution to journalArticleResearchpeer-review

19 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

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