Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome
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2017-03-06
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Journal of Experimental Medicine (JEM)
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ROCKEFELLER UNIV PRESS
Melbourne Authors
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School of Mathematics and Statistics
Medical Biology (W.E.H.I.)
Medical Biology (W.E.H.I.)
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Witkowski, M. T., Hu, Y., Roberts, K. G., Boer, J. M., McKenzie, M. D., Liu, G. J., Le Grice, O. D., Tremblay, C. S., Ghisi, M., Willson, T. A., Horstmann, M. A., Aifantis, I., Cimmino, L., Frietze, S., den Boer, M. L., Mullighan, C. G., Smyth, G. K. & Dickins, R. A. (2017). Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome. Journal of Experimental Medicine, 214 (3), pp.773-791. https://doi.org/10.1084/jem.20160048.
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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.