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Type: Journal article
Title: Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome
Author: Witkowski, M.
Hu, Y.
Roberts, K.
Boer, J.
McKenzie, M.
Liu, G.
Le Grice, O.
Tremblay, C.
Ghisi, M.
Willson, T.
Horstmann, M.
Aifantis, I.
Cimmino, L.
Frietze, S.
den Boer, M.
Mullighan, C.
Smyth, G.
Dickins, R.
Citation: Journal of Experimental Medicine, 2017; 214(3):773-791
Publisher: Rockefeller University Press
Issue Date: 2017
ISSN: 0022-1007
Statement of
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, and Ross A. Dickins
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.
Keywords: Ikaros Transcription Factor
Rights: © 2017 Witkowski et al. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http ://www .rupress .org/terms /). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 4.0 International license, as described at
RMID: 0030082866
DOI: 10.1084/jem.20160048
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