Journal article
Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome
MT Witkowski, Y Hu, KG Roberts, JM Boer, MD McKenzie, GJ Liu, OD Le Grice, CS Tremblay, M Ghisi, TA Willson, MA Horstmann, I Aifantis, L Cimmino, S Frietze, ML den Boer, CG Mullighan, GK Smyth, RA Dickins
Journal of Experimental Medicine | ROCKEFELLER UNIV PRESS | Published : 2017
DOI: 10.1084/jem.20160048
Open access
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..
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Awarded by European Commission
Funding Acknowledgements
This work was supported by the National Health and Medical Research Council of Australia (NHMRC) project grants 1024599 and 1080183 (R.A. Dickins), Senior Research Fellowship (G.K. Smyth), and Early Career Fellowship (L. Cimmino), NHMRC IRI ISS, and Victorian State Government OIS grants. This work was supported in part by American Lebanese Syrian Associated Charities and National Cancer Institute grants CA21765 and CA145707 of St. Jude Children's Research Hospital; a Stand Up to Cancer Innovative Research Grant and St. Baldrick's Foundation Scholar Award (C.G. Mullighan); and an American Society of Hematology Scholar Award (K.G. Roberts). This work was also supported by Dutch Cancer Society grant EMCR 2007-3718 (M.L. den Boer), the Pediatric Oncology Foundation Rotterdam (M.L. den Boer and J.M. Boer), and the European Union's Seventh Framework Program/European Network for Cancer Research in Children and Adolescents grant HEALTH-F2-2011-261474 (M.L. den Boer). The work was also funded by the Leukaemia Foundation of Australia (scholarships to M.T. Witkowski and G.J. Liu; fellowship to M.D. McKenzie), a Sylvia and Charles Viertel Charitable Foundation Fellowship (R.A. Dickins), and a Victorian Endowment for Science, Knowledge and Innovation Fellowship (R.A. Dickins).