Unknown,Transcriptomics,Genomics,Proteomics

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Reversal of glucocorticoid resistance by AKT inhibition in T-ALL

ABSTRACT: Glucocorticoid resistance is a major driver of therapeutic failure in T-cell acute lymphoblastic leukemia (T-ALL). Here we used a systems biology approach, based on the reverse engineering of signaling regulatory networks, which identified the AKT1 kinase as a signaling factor driving glucocorticoid resistance in T-ALL. Indeed, activation of AKT1 in T-ALL lymphoblasts impairs glucocorticoid-induced apoptosis. Mechanistically, AKT1 directly phosphorylates the glucocorticoid receptor NR3C1 protein at position S134 and blocks glucocorticoid-induced NR3C1 translocation to the nucleus. Consistently, inhibition of AKT1 with MK-2206 increases the response of T-ALL cells to glucocorticoid therapy both in T-ALL cell lines and in primary patient samples thus effectively reversing glucocorticoid resistance in vitro and in vivo. These results warrant the clinical testing of ATK1 inhibitors and glucocorticoids, in combination, for the treatment of T-ALL. This study includes 228 T-ALL samples of which 117 samples are re-analysis of GSE26713.

ORGANISM(S): Homo sapiens

SUBMITTER: Jules Meijerink

PROVIDER: E-GEOD-32215 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnormalities, some occurring in a mutually exclusive manner possibly delineating specific T-ALL subgroups. One subgroup, including MLL-rearranged, CALM-AF10 or inv(7)(p15q34) cases, is characterized by elevated expression of HOXA genes. Using a gene expression based clustering analysis of 67 T-ALL cases with recurrent molecular genetic abnormalities and 25 samples lacking apparent aberrations, we identified 5 new cases with elevated HOXA levels. Using array-CGH, a cryptic and recurrent deletion, del(9)(q34.11q34.13), was exclusively identified in 3 of these 5 cases. This deletion results in a conserved SET-NUP214 fusion product, that was also identified in the T-ALL cell line LOUCY. SET-NUP214 binds in the promoter regions of specific HOXA genes, where it may interact with CRM1 and DOT1L leading to the transcriptional activation of HOXA genes. Targeted inhibition of SET-NUP214 by siRNA abolished expression of HOXA genes, inhibited proliferation and induced differentiation in LOUCY but not in other T-ALL lines. We conclude that SET-NUP214 may contribute to the pathogenesis of T-ALL by enforcing T-cell differentiation arrest. We combined gene expression profiling and array-CGH analysis to detect a new and recurrent molecular cytogenetic abnormality in T-ALL patients that co-clustered with 5 well-defined HOXA-activated T-ALL samples. We describe the cloning of a recurrent SET-NUP214 fusion product in these samples, and identified a potential mechanism by which SET-NUP214 may activate the HOXA gene cluster as potential leukemogenic event in T-ALL. Experiment Overall Design: For 67 T-ALL patients having one of the major molecular cytogenetic abnormalities (i.e. TAL1 (n=24), LMO2 (n=9), HOXA (n=5), HOX11/TLX1 (n=7), and HOX11L2/TLX3 (n=22)), differentially expressed probesets were calculated from Affymetrix U133plus2.0 data based upon a Wilcoxon analysis and corrected for multiple testing for each probeset. Significant and differentially expressed probesets were obtained for the TAL1, HOX11 and HOX11L2 subgroups. No significant probesets were obtained for the HOXA subgroup or the LMO2 subgroup . As TAL1 and LMO2 both participate in the same transcriptional complex, activation of these genes may both lead to a highly similar expression profile. Combined analysis of TAL1 and LMO2 rearranged cases revealed significant and differentially expressed probesets that, as expected, almost entirely overlapped with the gene signature obtained for the TAL1-subgroup only. Next, we clustered 92 T-ALL cases, that besides the 67 cases as described above further included 25 T-ALL that lacked any of these recurrent abnormalities. Cluster analysis was performed based upon the top 25, 50 or 100 most significant probesets for the TAL1, TAL1/LMO2, HOX11 and HOX11L2 subgroups combined with 15 HOXA probesets identified by Soulier et al (2005)

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Reversal of glucocorticoid resistance by AKT inhibition in T-ALL

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