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Integrative Epigenomic Analysis Identifies Biomarkers and Therapeutic Targets in Adult B-Acute Lymphoblastic Leukemia

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Integrative Epigenomic Analysis Identifies Biomarkers and Therapeutic Targets in Adult B-Acute Lymphoblastic Leukemia Published OnlineFirst October 29, 2012; DOI: 10.1158/2159-8290.CD-12-0208 RESEARCH ARTICLE Integrative Epigenomic Analysis Identifi es Biomarkers and Therapeutic Targets in Adult B-Acute Lymphoblastic Leukemia Huimin Geng 1 , 2 , 8 , Sarah Brennan 1 , Thomas A. Milne 3 , 10 , Wei-Yi Chen 4 , Yushan Li 1 , Christian Hurtz 7 , 8 , 15 , Soo-Mi Kweon 7 , Lynette Zickl 9 , Seyedmehdi Shojaee 7 , 8 , Donna Neuberg 9 , Chuanxin Huang 1 , Debabrata Biswas 4 , Yuan Xin 1 , Janis Racevskis 6 , Rhett P. Ketterling 11 , Selina M. Luger 12 , Hillard Lazarus 14 , Martin S. Tallman 5 , Jacob M. Rowe 13 , Mark R. Litzow 11 , Monica L. Guzman 1 , C. David Allis 3 , Robert G. Roeder 4 , Markus Müschen 7 , 8 , Elisabeth Paietta 6 , Olivier Elemento 2 , and Ari M. Melnick 1 Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst October 29, 2012; DOI: 10.1158/2159-8290.CD-12-0208 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 pat- terning 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 tar- gets. We therefore conducted DNA methylation and gene expression profi ling 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 defi ned 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 regard- less of BCR–ABL1 status, suggesting CD25 as a novel prognostic biomarker for risk stratifi cation 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. MLL r B-ALL featured prominent cytosine hypomethylation, which was linked with MLL fusion protein binding, H3K79 dimethylation, and transcriptional upregula- tion, affecting a set of known and newly identifi ed MLL fusion direct targets with oncogenic activity such as FLT3 and BCL6 . Notably, BCL6 blockade or loss of function suppressed proliferation and survival of MLL r leukemia cells, suggesting BCL6-targeted therapy as a new therapeutic strategy for MLL r B-ALLs. SIGNIFICANCE: We conducted the fi rst integrative epigenomic study in adult B-ALLs, as a correlative study to the ECOG E2993 phase III clinical trial. This study links for the fi rst 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 infl ammatory 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. Cancer Discov; 2(11); 1–20. ©2012 AACR. INTRODUCTION each of these B-ALL subtypes features distinct and per- turbed gene expression profi les as compared with each other Adult B-cell precursor acute lymphoblastic leukemia and to normal pre-B cells ( 3–6 ). A deeper understanding of (B-ALL) is an aggressive disease with a less than 40% long- the mechanisms driving aberrant gene expression as well as term survival rate ( 1 ). This relatively poor outcome compared improved biomarkers and therapeutic targets are needed to with childhood B-ALLs is partly explained by an increased improve risk stratifi cation and therapy. frequency of high-risk molecular lesions such as BCR–ABL1 Transcriptional regulation and hence cellular phenotypes (20%–40% in adults vs. 2%–5% in children), MLL rearrange- are increasingly understood to be programmed by epigenetic ments ( MLLr , 10%–20%), and E2A–PBX1 fusions (5%; refs. 1, modifi cations of chromatin ( 7, 8 ). Epigenetic information is 2 ). The molecular mechanisms underlying poor outcome in encoded, in large part, by patterns of cytosine methylation and these adult B-ALLs are only partially understood. However, histone modifi cations. An increased abundance of cytosine Authors’ Affi liations: 1 Department of Medicine/Hematology-Oncology Pennsylvania; 13 Department of Hematology and BMT, Rambam Medical Division, 2 Institute for Computational Biomedicine, Weill Medical College Center, Haifa, Israel; 14 Department of Medicine, Case Western Reserve of Cornell University; 3 Laboratory of Chromatin Biology and Epigenet- University, Cleveland, Ohio; and 15 Max Planck Institute for Immunobiology, ics, 4 Laboratory of Biochemistry and Molecular Biology, the Rockefeller Freiburg, Germany 5 University; Department of Medicine, Memorial Sloan-Kettering Cancer Note: Supplementary data for this article are available at Cancer Discovery 6 Center, New York; Montefi ore Medical Center, Albert Einstein College of Online (http://cancerdiscovery.aacrjournals.org/). Medicine, Bronx, New York, New York; 7 Children’s Hospital Los Angeles, Corresponding Authors: Ari Melnick, Division of Hematology/Oncology, University of Southern California, Los Angeles; 8 Department of Labo- Department of Medicine, Weill Cornell Medical College, 1300 York Ave, ratory Medicine, University of California San Francisco, San Francisco, New York, NY 10065. Phone: 212-746-7643; Fax: 212-746-8866; E-mail: California; 9 Dana Farber Cancer Institute, Boston, Massachusetts; 10 MRC [email protected] ; Olivier Elemento. E-mail: ole2001@med. Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, cornell.edu; and Elisabeth Paietta. E-mail: [email protected] University of Oxford, Headington, Oxford, United Kingdom; 11 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minne- doi: 10.1158/2159-8290.CD-12-0208 sota; 12 Abramson Cancer Center, University of Pennsylvania, Philadelphia, © 2012 American Association for Cancer Research. NOVEMBER 2012CANCER DISCOVERY | OF2 Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2012 American Association for Cancer Research. Published OnlineFirst October 29, 2012; DOI: 10.1158/2159-8290.CD-12-0208 RESEARCH ARTICLE Geng et al. methylation at gene promoters, especially those contain- RESULTS ing CpG islands, is generally associated with transcriptional Specifi c Promoter DNA Methylation Patterning silencing, whereas decreased cytosine methylation may facili- in Genetically Defi ned B-ALL Subtypes tate transcriptional activation. Importantly, perturbations in cytosine methylation patterning are epigenetically retained We reasoned that cytosine methylation patterning would during cell division, enabling dividing cells to transmit tran- provide biologically and clinically signifi cant information scriptional programming to their progeny ( 7, 8 ). This process about B-ALLs in adult patients. Therefore, we conducted allows cells within tissues including tumors to retain their HELP (HpaII tiny fragment enrichment by ligation-mediated specifi c phenotypes. Along these lines, DNA methylation pat- PCR) DNA methylation assays ( 31 ) on a cohort of 215 newly terning has been shown to shift during normal hematopoiesis diagnosed adult patients with B-ALLs with available diagnos- and is believed to play an essential role in lineage specifi ca- tic specimens enrolled in the ECOG E2993 multicenter phase tion ( 9 ). Accordingly, disruption of the function of DNA III clinical trial (Supplementary Tables S1 and S2 for detailed methyltransferases (DNMT) perturbs normal hematopoiesis patient description). Eighty-three of these patients featured ( 10, 11 ). By the same token, DNA methylation patterning BCR–ABL1 translocations, 7 had E2A–PBX1 fusions, and 28 of terminally differentiated cells must be erased for them to harbored MLL rearrangements. We focused our attention return to a pluripotent and self-renewal state ( 12, 13 ). Similar principally on these B-ALLs because of their defi ned genetic to normal tissues, tumors may be dependent on specifi c DNA background and association with poor clinical outcome. We methylation patterns to acquire their unique phenotypes also profi led normal pre-B cells (CD19+ and VpreB + ) isolated ( 14 ). Characterization of cytosine methylation patterning in from the bone marrows of 12 healthy adults as normal tumors may thus provide important insights into how gene counterpart for our B-ALL tumor samples (Supplementary expression is perturbed in different tumor types. Table S2). HELP was conducted using a customized micro- Identifi cation of epigenetically modifi ed genes may be array design covering more than 50,000 CpGs annotated highly informative, as deregulation of key signaling or tran- to 14,000 gene promoters and our standard quality control scriptional regulatory genes can alter entire downstream and normalization algorithms ( 31–33 ). We conducted tech- pathways and have signifi cant biologic effects. For example, nical validation
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