Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome
Details
Publication Year 2017-02-11, Volume 214, Issue #3, Page 773-791
Journal Title
J Exp Med
Publication Type
Journal Article
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.
Publisher
Rockefeler Uni Press
WEHI Research Division(s)
Molecular Medicine; Bioinformatics
PubMed ID
28190000
NHMRC Grants
NHMRC/1024599 NHMRC/1080183
Rights Notice
Refer to copyright notice on published article.


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