title: Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome.
abstract: Genetic alterations disrupting the transcription factorIKZF1(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 areEMP1, which was recently implicated in B-ALL proliferation and prednisolone resistance, and the novel targetCTNND1, encoding P120-catenin. We demonstrate that elevated Ctnnd1 expression contributes to maintenance of murine B-ALL cells with compromised Ikaros function. These results suggest thatIKZF1alterations in B-ALL leads to induction of multiple genes associated with proliferation and treatment resistance, identifying potential new therapeutic targets for high-risk disease.
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.|Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville 3010, Victoria, Australia.
authors.forename: Matthew T
authors.identifier: 0000-0002-5019-0119
authors.initials: MT
authors.lastname: Witkowski
authors.affiliation: Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.
authors.forename: Yifang
authors.identifier: 0000-0001-8200-0052
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Kathryn G
authors.initials: KG
authors.lastname: Roberts
authors.affiliation: Department of Pediatric Oncology, Erasmus MC - Sophia Children's Hospital, 3015 CN Rotterdam, Netherlands.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Boer
authors.affiliation: Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville 3010, Victoria, Australia.
authors.forename: Mark D
authors.initials: MD
authors.lastname: McKenzie
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.|Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville 3010, Victoria, Australia.
authors.forename: Grace J
authors.initials: GJ
authors.lastname: Liu
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.|Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.
authors.forename: Oliver D
authors.identifier: 0000-0001-5557-769X
authors.initials: OD
authors.lastname: Le Grice
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Cedric S
authors.identifier: 0000-0003-2396-776X
authors.initials: CS
authors.lastname: Tremblay
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Margherita
authors.initials: M
authors.lastname: Ghisi
authors.affiliation: Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.
authors.forename: Tracy A
authors.identifier: 0000-0003-4833-7342
authors.initials: TA
authors.lastname: Willson
authors.affiliation: Research Institute Children's Cancer Center, Department of Pediatric Hematology and Oncology, University Medical Center Hamburg, 20246 Hamburg, Germany.
authors.forename: Martin A
authors.identifier: 0000-0001-8559-8862
authors.initials: MA
authors.lastname: Horstmann
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY 10016.
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY 10016.
authors.forename: Luisa
authors.identifier: 0000-0002-8729-6435
authors.initials: L
authors.lastname: Cimmino
authors.affiliation: Department of Medical Laboratory and Radiation Science, University of Vermont, Burlington, VT 05405.
authors.forename: Seth
authors.initials: S
authors.lastname: Frietze
authors.affiliation: Department of Pediatric Oncology, Erasmus MC - Sophia Children's Hospital, 3015 CN Rotterdam, Netherlands.|Dutch Childhood Oncology Group, 2545 The Hague, Netherlands.
authors.forename: Monique L
authors.identifier: 0000-0002-5795-2921
authors.initials: ML
authors.lastname: den Boer
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.affiliation: Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.|Department of Mathematics and Statistics, University of Melbourne, Parkville 3010, Victoria, Australia.
authors.forename: Gordon K
authors.identifier: 0000-0001-9221-2892
authors.initials: GK
authors.lastname: Smyth
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia ross.dickins@monash.edu.|Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville 3010, Victoria, Australia.
authors.forename: Ross A
authors.identifier: 0000-0003-4112-5304
authors.initials: RA
authors.lastname: Dickins
mesh_terms: D000818:Animals; D051177:Catenins / Q000235:genetics; D045744:Cell Line, Tumor; D016044:Fusion Proteins, bcr-abl / Q000032:analysis; D006801:Humans; D051740:Ikaros Transcription Factor / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D000095002:Delta Catenin
chemical_list: C581634:BCR-ABL1 fusion protein, human; D051177:Catenins; C080082:IFITM3 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D011956:Receptors, Cell Surface; C097051:epithelial membrane protein-1; D051740:Ikaros Transcription Factor; D016044:Fusion Proteins, bcr-abl; D000095002:Delta Catenin