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


Witkowski, MT; Hu, Y; Roberts, KG; Boer, JM; McKenzie, MD; Liu, GJ; Le Grice, OD; Tremblay, CS; Ghisi, M; Willson, TA; Horstmann, MA; Aifantis, I; Cimmino, L; Frietze, S; den Boer, ML; Mullighan, CG; Smyth, GK; Dickins, RA
2017-02-11
J Exp Med
Journal Article
214
3
773-791
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.
Rockefeler Uni Press
Molecular Medicine; Bioinformatics
10.1084/jem.20160048
28190000
Refer to article for additional funding acknowledgements
Refer to copyright notice on published article.

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Creation Date 2017-04-06 09:27:13 Last Modified 2017-04-07 03:24:09