Epigenome-wide analysis reveals functional modulators of drug sensitivity and post-treatment survival in chronic lymphocytic leukaemia

Abstract

BACKGROUND: Chronic lymphocytic leukaemia (CLL) patients display a highly variable clinical course, with progressive acquisition of drug resistance. We sought to identify aberrant epigenetic traits that are enriched following exposure to treatment that could impact patient response to therapy. METHODS: Epigenome-wide analysis of DNA methylation was performed for 20 patients at two time-points during treatment. The prognostic significance of differentially methylated regions (DMRs) was assessed in independent cohorts of 139 and 163 patients. Their functional role in drug sensitivity was assessed in vitro. RESULTS: We identified 490 DMRs following exposure to therapy, of which 31 were CLLspecific and independent of changes occurring in normal B-cell development. Seventeen DMR-associated genes were identified as differentially expressed following treatment in an independent cohort. Methylation of the HOXA4, MAFB and SLCO3A1 DMRs were associated with post-treatment patient survival, with HOXA4 displaying the strongest association. Re-expression of HOXA4 in cell lines and primary CLL cells significantly increased apoptosis in response to treatment with fludarabine, ibrutinib and idelalisib.CONCLUSION: Our study demonstrates enrichment for multiple CLL-specific epigenetic traits in response to chemotherapy that predict patient outcomes, and particularly implicate epigenetic silencing of HOXA4 in reducing the sensitivity of CLL cells to therapy.

Signature Panel of 11 Methylated mRNAs and 3 Methylated lncRNAs for Prediction of Recurrence-Free Survival in Prostate Cancer Patients

“…The transcript of SLCO3A1 was also observed to be increased following treatment with 5-Aza-dC. 38 NTRK3 methylation silenced NTRK3 expression which induced neoplastic transformation in vitro and tumor growth in vivo; reconstitution of NTRK3 induced apoptosis in colorectal cancers. 43 DNA methylation profiling analysis and validation experiments showed that NAV1 was significantly hypomethylated in breast cancers; 44 while overexpression of members of the neuron navigator gene family was reported to promote invasion and predict poor prognosis.…”

“… 37 Higher methylation level of SLCO3A1 (also known as OATP3A1) was associated with shorter post-treatment survival of patients with chronic lymphocytic leukaemia. 38 Univariate Cox regression and Kaplan–Meier survival analyses showed that high methylation located in NTRK3 gene was significantly associated with poor prognosis in patients with esophageal squamous cell carcinoma (HR = 1.79). 39 In agreement with these studies, we also found that patients with a high methylation level of MEG3 (HR = 1.18), SLCO3A1 (HR = 5.852) and NTRK3 (HR = 4.930) were at a higher risk of having unfavorable RFS.…”

“…37 Higher methylation level of SLCO3A1 (also known as OATP3A1) was associated with shorter posttreatment survival of patients with chronic lymphocytic leukaemia. 38 Univariate Cox regression and Kaplan-Meier survival analyses showed that high methylation located in NTRK3 gene was significantly associated with Figure 5 The co-expression network between differentially methylated lncRNAs and mRNAs identified unstable modules. The color indicated the corresponding module.…”

Anti-cancer therapy is associated with long-term epigenomic changes in childhood cancer survivors

“…For example, we have previously determined that exposure to chemotherapy leads to increased levels of DNA methylation at the HOXA4 locus in remission samples from both adult and childhood ALL [ 15 ], a finding that was replicated here. In addition, we have demonstrated that treatment of chronic lymphocytic leukaemia patients, results in selection for altered methylation of a number of genes, including hypermethylation of HOXA4 , in the leukaemia cells [ 32 ]. Restoration of HOXA4 expression re-sensitises CLL cells to multiple therapeutic agents, identifying a direct role for HOXA4 in control of sensitivity to chemotherapeutic agents with different mechanisms of action [ 32 ].…”

KB-68A7.1 Inhibits Hepatocellular Carcinoma Development Through Binding to NSD1 and Suppressing Wnt/β-Catenin Signalling

“…Although some genomic mutations have been found in HCC, more genes with aberrant expression accumulate in HCC (7)(8)(9). Epigenetic modulation is one of the critical mechanisms contributing to the dysregulated expression of genes (10)(11)(12). As one of the epigenetic modulation manners, histone methylation modification exerts multiple effects on gene transcription (13)(14)(15).…”