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

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.

Targeting Aurora B kinase with Tanshinone IIA suppresses tumor growth and overcomes radioresistance

“…Moreover, suppression of Aurora B enhances the efficacy of radiotherapy 28,29 and overcomes acquired resistance in EGFR targeting therapy 30 . In addition, overexpression of Aurora B causes relapse of B cell acute lymphoblastic leukemia and blunts the glucocorticoid sensitivity 31 . Here, we found that Aurora B is highly expressed in human OSCC tumor tissues and cancer cells.…”

Pressure regulated basis for gene transcription by delta-cell micro-compliance modeled in silico: Biphenyl, bisphenol and small molecule ligand models of cell contraction-expansion

“…In the A549 lung carcinoma/HepG2 HCC cell model for AhR gene reporter plasmid expression [ 64 ] , applied TGFβ1 results in activation of z , x -plane transcription-ready plasmid upon endogenous TGIF1 transcription at P eff 0.080 as the SMAD co-adapter is required for RNA polymerase transcription, however without the need for applied TGFβ1 in A549 cells that demonstrate a bidirectional negative expansion Δ C micro response P eff of 0.080 as compared the nadir for HepG2 cells, which would between P eff 0.130 ( LGAL1 ) and 0.106 ( UGT1A1 ). The in vitro application of aldosterone (Ald) to SkBr3 mammary carcinoma and tumor-associated endothelial cells results in the transcriptional overactivation of GPER1 (GPR30; P eff 0.376) and SLC9A1 (NHE-1, P eff 0.167) [ 130 ] , and will result in an increase in GR expression concomitantly ( NR3C1 , P eff 0.376) ( Table 10 ), with an increase in pEGFR/ERK1,2 levels as part of the negative C micro expansion response phase, as will occur with application of a combination of E 2 and inverse agonist(s) [ 131 ] with a resultant equivalent increase in intracellular pressure to P eff 0.112 at which CYP11B2 (Ald Synthase) transcription increases at P eff during Δ C micro contraction; whereas, the in vivo application of Dex (~Corticosterone) to normal adrenocortical cells results in a 0.5x-fold decrease in CYP11B1 (11-β-hydroxylase; P eff 0.099) decrease at duration at P eff while an increase with ACTH [ 132 ] , while GABPA ( P eff 0.494) and TSPAN14 ( P eff 0.057) increase in duration at P eff during maintained sensitivity to Dex at CM GR in human B-cell ALL in a viro-transformed cell type [ 133 ] , which reaffirms P eff 0.057 as the maximum lower limit of the contraction-negative P eff C micro expansion response to positive P eff regulation away from P eff 0.088 ( Ighm ) [ 37 ] , 0.088 ( Ighm ) and 0.075 ( Ighg3 ) [ 134 ] . Since the maximum P eff C micro contraction-expansion response to Dex is at the lower limit of cell expansion P eff and equivalent to the Δ C micro response applied co -, ortho -planar PCB-153, this implies GRE and TRE site-tuned parallel pathway involvement (ie CAR, AR), as there is known GR · half-site GRE enhancement of THRB gene transcription [ 135 ] with the potential for JUN (FOS) recruitment of GR to half-site TRE [ 89 ] and regulation of DIO1 ( P eff 0.236) gene transcription at P...…”

SUMOylation regulates the protein network and chromatin accessibility at glucocorticoid receptor-binding sites

“…However, the molecular mechanism(s) by which SUMOylation influences TF binding/occupancy on chromatin have remained uncovered. In this work, by using chromatin immunoprecipitation with selective isolation of chromatin-associated proteins (ChIP-SICAP) and mass spectrometry (MS) from cells stably isotopically-labeled with amino acids in culture (SILAC) ( 18 ), we firstly uncover the composition of the chromatin protein network around the hormone-bound GR, which markedly overlaps with the factors important for the growth of B-ALL cells ( 19 ). Secondly, we show that the protein network is modulated by the SUMOylation status of GR.…”