Title | Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Geng H, Brennan S, Milne TA, Chen W-Y, Li Y, Hurtz C, Kweon S-M, Zickl L, Shojaee S, Neuberg D, Huang C, Biswas D, Xin Y, Racevskis J, Ketterling RP, Luger SM, Lazarus H, Tallman MS, Rowe JM, Litzow MR, Guzman ML, C Allis D, Roeder RG, Müschen M, Paietta E, Elemento O, Melnick AM |
Journal | Cancer Discov |
Volume | 2 |
Issue | 11 |
Pagination | 1004-23 |
Date Published | 2012 Nov |
ISSN | 2159-8290 |
Keywords | Biomarkers, Tumor, CD3 Complex, DNA Methylation, DNA-Binding Proteins, Epigenomics, Fusion Proteins, bcr-abl, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Histone-Lysine N-Methyltransferase, Homeodomain Proteins, Humans, Interleukin-2 Receptor alpha Subunit, Myeloid-Lymphoid Leukemia Protein, Oncogene Proteins, Fusion, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Promoter Regions, Genetic, Proto-Oncogene Proteins c-bcl-6 |
Abstract | UNLABELLED: Genetic lesions such as BCR-ABL1, E2A-PBX1, and MLL rearrangements (MLLr) are associated with unfavorable outcomes in adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Leukemia oncoproteins may directly or indirectly disrupt cytosine methylation patterning to mediate the malignant phenotype. We postulated that DNA methylation signatures in these aggressive B-ALLs would point toward disease mechanisms and useful biomarkers and therapeutic targets. We therefore conducted DNA methylation and gene expression profiling on a cohort of 215 adult patients with B-ALL enrolled in a single phase III clinical trial (ECOG E2993) and normal control B cells. In BCR-ABL1-positive B-ALLs, aberrant cytosine methylation patterning centered around a cytokine network defined by hypomethylation and overexpression of IL2RA(CD25). The E2993 trial clinical data showed that CD25 expression was strongly associated with a poor outcome in patients with ALL regardless of BCR-ABL1 status, suggesting CD25 as a novel prognostic biomarker for risk stratification in B-ALLs. In E2A-PBX1-positive B-ALLs, aberrant DNA methylation patterning was strongly associated with direct fusion protein binding as shown by the E2A-PBX1 chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq), suggesting that E2A-PBX1 fusion protein directly remodels the epigenome to impose an aggressive B-ALL phenotype. MLLr B-ALL featured prominent cytosine hypomethylation, which was linked with MLL fusion protein binding, H3K79 dimethylation, and transcriptional upregulation, affecting a set of known and newly identified MLL fusion direct targets with oncogenic activity such as FLT3 and BCL6. Notably, BCL6 blockade or loss of function suppressed proliferation and survival of MLLr leukemia cells, suggesting BCL6-targeted therapy as a new therapeutic strategy for MLLr B-ALLs. SIGNIFICANCE: We conducted the first integrative epigenomic study in adult B-ALLs, as a correlative study to the ECOG E2993 phase III clinical trial. This study links for the first time the direct actions of oncogenic fusion proteins with disruption of epigenetic regulation mediated by cytosine methylation. We identify a novel clinically actionable biomarker in B-ALLs: IL2RA (CD25), which is linked with BCR-ABL1 and an inflammatory signaling network associated with chemotherapy resistance. We show that BCL6 is a novel MLL fusion protein target that is required to maintain the proliferation and survival of primary human adult MLLr cells and provide the basis for a clinical trial with BCL6 inhibitors for patients with MLLr. |
DOI | 10.1158/2159-8290.CD-12-0208 |
Alternate Journal | Cancer Discov |
PubMed ID | 23107779 |
PubMed Central ID | PMC3516186 |
Grant List | R01 CA178765 / CA / NCI NIH HHS / United States G8223452 / / Medical Research Council / United Kingdom R01 CA157644 / CA / NCI NIH HHS / United States DP2 OD007399 / OD / NIH HHS / United States U10 CA023318 / CA / NCI NIH HHS / United States U24 CA114737 / CA / NCI NIH HHS / United States R01 CA104348 / CA / NCI NIH HHS / United States R01 CA143032 / CA / NCI NIH HHS / United States R01 CA137060 / CA / NCI NIH HHS / United States |