Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies

Abstract

Despite an increase in survival for children with acute lymphoblastic leukemia (ALL), the outcome after relapse is poor. To understand the genetic events that contribute to relapse and chemoresistance and identify novel targets of therapy, 3 high-throughput assays were used to identify genetic and epigenetic changes at relapse. Using matched diagnosis/ relapse bone marrow samples from children with relapsed B-precursor ALL, we evaluated gene expression, copy number abnormalities (CNAs), and DNA methylation. Gene expression analysis revealed a signature of differentially expressed genes from diagnosis to relapse that is different for early (< 36 months) and late (> 36 months) relapse. CNA analysis discovered CNAs that were shared at diagnosis and relapse and others that were new lesions acquired at relapse. DNA methylation analysis found increased promoter methylation at relapse. There were many genetic alterations that evolved from diagnosis to relapse, and in some cases these genes had previously been associated

Loss of TBL1XR1 Disrupts Glucocorticoid Receptor Recruitment to Chromatin and Results in Glucocorticoid Resistance in a B-Lymphoblastic Leukemia Model

“…We observed a significant decrease in TBL1XR1 gene expression at relapse compared diagnosis ( Table 1). The overall expression of TBL1XR1 at relapse compared with diagnosis was not changed (ratio 1.084 Ϯ 0.0540) in a cohort of 49 matched pairs (46 with overlapping copy number data plus an additional 3 patients with only gene expression data) (data not shown) (6). Furthermore, CpG promoter methylation of the TBL1XR1 gene is not altered at relapse compared with diagnosis (data not shown) (6).…”

“…We and others have described recurrent deletions with concordant decreased gene expression in TBL1XR1 at relapse (6,7). TBL1XR1 deletions are enriched at relapse compared with diagnosis (6 -8), and importantly TBL1XR1 deletions at diagnosis occur more frequently in patients that ultimately relapse (9).…”

“…The degradation of the NCoR complex by TBL1XR1 is required for gene activation by many liganded nuclear receptors, as well as other transcription factors (10 -14). Relapse-specific mutations in NCoR1 (15), as well as increased expression of the enzymatically active members of the NCoR complex, histone deacetylases (HDACs), have also been described in relapsed ALL (6). Increased expression of HDAC3, HDAC4, HDAC7, and HDAC9 correlate with a poor prognosis when noted at diagnosis (16,17).…”

“…The overall expression of TBL1XR1 at relapse compared with diagnosis was not changed (ratio 1.084 Ϯ 0.0540) in a cohort of 49 matched pairs (46 with overlapping copy number data plus an additional 3 patients with only gene expression data) (data not shown) (6). Furthermore, CpG promoter methylation of the TBL1XR1 gene is not altered at relapse compared with diagnosis (data not shown) (6). This suggests that decreased gene expression at relapse is only seen in the subset of patients harboring a TBL1XR1 deletion and that other mechanisms to decrease expression are not operative.…”

“…Relapse in Primary ALL Samples-We have previously established an integrated genomics profile of relapsed ALL (6). Through this study, we and others have identified focal deletions in TBL1XR1 in ϳ10.7% of patients at relapse (6, 7).…”