Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome
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.
|Persistent URL||dx.doi.org/10.1084/jem.20160048, hdl.handle.net/1765/108126|
|Journal||The Journal of experimental medicine|
Witkowski, M.T. (Matthew T.), Hu, Y. (Yifang), Roberts, K.G. (Kathryn G.), Boer, J.M. (Judith M.), McKenzie, M.D. (Mark D.), Liu, G.J. (Grace J.), … Dickins, R.A. (Ross A.). (2017). Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome. The Journal of experimental medicine, 214(3), 773–791. doi:10.1084/jem.20160048