Relapse-associated AURKB blunts the glucocorticoid sensitivity of B cell acute lymphoblastic leukemia

Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):3052-3061. doi: 10.1073/pnas.1816254116. Epub 2019 Feb 7.


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.

Keywords: AURKB; cell death; coregulator; glucocorticoid; leukemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinase B / genetics*
  • Cell Death / genetics*
  • Cell Line, Tumor
  • Chromosomal Proteins, Non-Histone / genetics
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression Regulation, Leukemic / genetics
  • Glucocorticoids / genetics
  • Glucocorticoids / pharmacology
  • Histocompatibility Antigens / genetics
  • Histone-Lysine N-Methyltransferase / genetics
  • Humans
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • RNA, Small Interfering / genetics
  • Recurrence


  • CBX3 protein, human
  • Chromosomal Proteins, Non-Histone
  • Glucocorticoids
  • Histocompatibility Antigens
  • RNA, Small Interfering
  • EHMT1 protein, human
  • EHMT2 protein, human
  • Histone-Lysine N-Methyltransferase
  • AURKB protein, human
  • Aurora Kinase B