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 J Liu, Oliver D Le Grice, Cedric S Tremblay, Margherita Ghisi, Tracy A Willson, Martin A Horstmann, Iannis Aifantis, Luisa Cimmino, Seth Frietze, Monique L den Boer, Charles G Mullighan, Gordon K Smyth, Ross A Dickins

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)773-791
Aantal pagina's19
TijdschriftThe Journal of experimental medicine
Volume214
Nummer van het tijdschrift3
DOI's
StatusGepubliceerd - 6 mrt. 2017
Extern gepubliceerdJa

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