Journal article
Relapse-associated AURKB blunts the glucocorticoid sensitivity of B cell acute lymphoblastic leukemia
Proceedings of the National Academy of Sciences - PNAS, Vol.116(8), pp.3052-3061
02/19/2019
DOI: 10.1073/pnas.1816254116
PMCID: PMC6386662
PMID: 30733284
Abstract
Glucocorticoids (GCs) are used in combination chemotherapies as front-line treatment for B cell acute lymphoblastic leukemia (B-ALL). Although effective, many patients relapse and become resistant to chemotherapy and GCs in particular. Why these patients relapse is not clear. We took a comprehensive, functional genomics approach to identify sources of GC resistance. A genome-wide shRNA screen identified the transcriptional coactivators EHMT2, EHMT1, and CBX3 as important contributors to GC-induced cell death. This complex selectively supports GC-induced expression of genes contributing to cell death. A metaanalysis of gene expression data from B-ALL patient specimens revealed that Aurora kinase B (AURKB), which restrains GC signaling by phosphorylating EHMT1-2, is overexpressed in relapsed B-ALL, suggesting it as a potential contributor to relapse. Inhibition of AURKB enhanced GC-induced expression of cell death genes, resulting in potentiation of GC cytotoxicity in cell lines and relapsed B-ALL patient samples. This function for AURKB is distinct from its canonical role in the cell cycle. These results show the utility of functional genomics in understanding mechanisms of resistance and rapidly identifying combination chemotherapeutics.
Details
- Title: Subtitle
- Relapse-associated AURKB blunts the glucocorticoid sensitivity of B cell acute lymphoblastic leukemia
- Creators
- Coralie Poulard - University of Southern CaliforniaHye Na Kim - Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033Mimi Fang - University of IowaKarina Kruth - University of IowaCeline Gagnieux - University of Southern CaliforniaDaniel S Gerke - University of Southern CaliforniaDeepa Bhojwani - Children's Hospital of Los AngelesYong-Mi Kim - Children's Hospital of Los AngelesMartin Kampmann - University of California, San FranciscoMichael R Stallcup - University of Southern CaliforniaMiles A Pufall - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.116(8), pp.3052-3061
- DOI
- 10.1073/pnas.1816254116
- PMID
- 30733284
- PMCID
- PMC6386662
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Grant note
- R00 CA149088 / NCI NIH HHS R00 CA181494 / NCI NIH HHS R37 DK055274 / NIDDK NIH HHS R01 CA172896 / NCI NIH HHS K99 CA181494 / NCI NIH HHS P30 CA014089 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 DK043093 / NIDDK NIH HHS
- Language
- English
- Date published
- 02/19/2019
- Academic Unit
- Psychiatry; Biochemistry and Molecular Biology
- Record Identifier
- 9984288716802771
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