Conserved IKAROS-regulated genes associated with B-progenitor acute lymphoblastic leukemia outcome

Author:

Witkowski Matthew T.123ORCID,Hu Yifang4ORCID,Roberts Kathryn G.5,Boer Judith M.6,McKenzie Mark D.23,Liu Grace J.123,Le Grice Oliver D.12ORCID,Tremblay Cedric S.1ORCID,Ghisi Margherita1,Willson Tracy A.2ORCID,Horstmann Martin A.7ORCID,Aifantis Iannis8,Cimmino Luisa8ORCID,Frietze Seth9,den Boer Monique L.610ORCID,Mullighan Charles G.5,Smyth Gordon K.411ORCID,Dickins Ross A.123ORCID

Affiliation:

1. Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia

2. Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Victoria, Australia

3. Department of Medical Biology, University of Melbourne, Parkville 3010, Victoria, Australia

4. Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Victoria, Australia

5. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN 38105

6. Department of Pediatric Oncology, Erasmus MC - Sophia Children’s Hospital, 3015 CN Rotterdam, Netherlands

7. Research Institute Children’s Cancer Center, Department of Pediatric Hematology and Oncology, University Medical Center Hamburg, 20246 Hamburg, Germany

8. Department of Pathology, NYU School of Medicine, New York, NY 10016

9. Department of Medical Laboratory and Radiation Science, University of Vermont, Burlington, VT 05405

10. Dutch Childhood Oncology Group, 2545 The Hague, Netherlands

11. Department of Mathematics and Statistics, University of Melbourne, Parkville 3010, Victoria, Australia

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.

Funder

National Health and Medical Research Council of Australia

National Cancer Institute

Stand Up to Cancer

American Society of Hematology

Dutch Cancer Society

Pediatric Oncology Foundation Rotterdam

Leukaemia Foundation of Australia

Sylvia and Charles Viertel Charitable Foundation

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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