title: Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine/Hematology-Oncology Division, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.forename: Sarah
authors.initials: S
authors.lastname: Brennan
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Milne
authors.forename: Wei-Yi
authors.initials: WY
authors.lastname: Chen
authors.forename: Yushan
authors.initials: Y
authors.lastname: Li
authors.forename: Christian
authors.initials: C
authors.lastname: Hurtz
authors.forename: Soo-Mi
authors.initials: SM
authors.lastname: Kweon
authors.forename: Lynette
authors.initials: L
authors.lastname: Zickl
authors.forename: Seyedmehdi
authors.initials: S
authors.lastname: Shojaee
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Chuanxin
authors.initials: C
authors.lastname: Huang
authors.forename: Debabrata
authors.initials: D
authors.lastname: Biswas
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xin
authors.forename: Janis
authors.initials: J
authors.lastname: Racevskis
authors.forename: Rhett P
authors.initials: RP
authors.lastname: Ketterling
authors.forename: Selina M
authors.initials: SM
authors.lastname: Luger
authors.forename: Hillard
authors.initials: H
authors.lastname: Lazarus
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Rowe
authors.forename: Mark R
authors.initials: MR
authors.lastname: Litzow
authors.forename: Monica L
authors.initials: ML
authors.lastname: Guzman
authors.forename: C David
authors.initials: CD
authors.lastname: Allis
authors.forename: Robert G
authors.initials: RG
authors.lastname: Roeder
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Paietta
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D017252:CD3 Complex / Q000096:biosynthesis; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D057890:Epigenomics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D051560:Proto-Oncogene Proteins c-bcl-6
chemical_list: C084103:BCL6 protein, human; D014408:Biomarkers, Tumor; D017252:CD3 Complex; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; C497422:KMT2A protein, human; D015514:Oncogene Proteins, Fusion; D051560:Proto-Oncogene Proteins c-bcl-6; C089847:E2A-Pbx1 fusion protein; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D016044:Fusion Proteins, bcr-abl