Inhibiting Aurora Kinase B Sensitizes B-Cell Acute Lymphoblastic Leukemia to Glucocorticoids

Glucocorticoids (GCs) are a component of first-line chemotherapy for many hematologic cancers because they induce cell death specifically in lymphoid cells. Most patients respond favorably, but some are resistant or develop resistance. Resistance is strongly correlated with glucocorticoid insensitivity, suggesting that enhancing GC-induced cell death can improve treatment.

GCs activate the glucocorticoid receptor, which binds specific DNA regulatory elements and recruits coregulators. Coregulators remodel chromatin and regulate the assembly of the transcriptional machinery. Our studies have focused on the cofactors G9a and GLP, lysine methyltransferases that are established corepressors. We showed in A549 lung adenocarcinoma cells that they also act as both coactivators and coreressors in a gene-specific fashion. Self-methylation in the N-terminal coactivator region provides a binding site for HP1g, which is required as a cooperating coactivator for G9a and GLP. In contrast, we have found that phosphorylation of the adjacent threonine by Aurora kinase B (AurkB) prevents binding to HP1g and reduces coactivator function of G9a and GLP (Poulard et al, EMBO Rep 2017 PMID:28615290). Thus, these adjacent modifications regulate coactivator function and contribute to determining whether G9a and GLP act as coactivators or corepressors.

A role for G9a and GLP coactivator function in GC-induced lymphoid cell death was suggested from a genome-wide shRNA screen in the NALM6 B-ALL cell line, which identified genes that make the cells more or less sensitive to the synthetic, clinically relevant GC dexamethasone (dex). Depletion of G9a (EHMT2), GLP (EHMT1), or HP1g (CBX3) made cells less sensitive to dex-induced cell death, while depletion of AurkB made cells more sensitive.

A microarray analysis for NALM6 cells containing or depleted of G9a or GLP revealed a subset of genes dependent upon G9a and GLP for robust dex-induced expression. In Gene Ontology analysis of these genes, the highest-scoring pathway was Cell Death and Survival. HP1g, in addition to G9a and GLP, was required for dex-induced expression of genes that cause cell death, confirming the same mechanism of G9a and GLP coactivator function in NALM6 cells. Moreover, AurkB inhibitors reduced G9a and GLP phosphorylation and increased sensitivity of NALM6 cells to dex-induced cell death. In support of the relevance of AurkB in B-ALL, AurkB mRNA levels were significantly higher in cells taken from relapsed patients and in patients who relapsed relatively quickly after initial treatment.

These finding suggest that GC potency can be enhanced by AurkB inhibition. Cotreatment of several cell lines with an AurkB inhibitor sensitized them to dex-induced cell death. Experiments in patient samples and xenograft models are underway to determine whether inhibition of AurkB is a general sensitizer of B-ALL to GCs and represents a potential treatment for resistant disease.