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Mutations in Epigenetic Regulators Including SETD2 Are Gained During Relapse in Paediatric Acute Lymphoblastic Leukaemia

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Mutations in Epigenetic Regulators Including SETD2 Are Gained During Relapse in Paediatric Acute Lymphoblastic Leukaemia ARTICLE Received 8 Oct 2013 | Accepted 18 Feb 2014 | Published 24 Mar 2014 DOI: 10.1038/ncomms4469 Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia Brenton G. Mar1,2, Lars B. Bullinger3, Kathleen M. McLean1, Peter V. Grauman4, Marian H. Harris5, Kristen Stevenson6, Donna S. Neuberg6, Amit U. Sinha7, Stephen E. Sallan1,2, Lewis B. Silverman1,2, Andrew L. Kung8, Luca Lo Nigro9, Benjamin L. Ebert4 & Scott A. Armstrong7 Relapsed paediatric acute lymphoblastic leukaemia (ALL) has high rates of treatment failure. Epigenetic regulators have been proposed as modulators of chemoresistance, here, we sequence genes encoding epigenetic regulators in matched diagnosis–remission–relapse ALL samples. We find significant enrichment of mutations in epigenetic regulators at relapse with recurrent somatic mutations in SETD2, CREBBP, MSH6, KDM6A and MLL2, mutations in signalling factors are not enriched. Somatic alterations in SETD2, including frameshift and nonsense mutations, are present at 12% in a large de novo ALL patient cohort. We conclude that the enrichment of mutations in epigenetic regulators at relapse is consistent with a role in mediating therapy resistance. 1 Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA. 2 Department of Hematology/Oncology, Boston Children’s Hospital, Boston, Massachusetts 02115, USA. 3 Department of Internal Medicine III, University of Ulm, Ulm 89081, Germany. 4 Division of Hematology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. 5 Department of Pathology, Boston Children’s Hospital, Boston, Massachusetts 02115, USA. 6 Biostatistics & Computational Biology, Dana Farber Cancer Institute, Boston, Massachusetts 02215, USA. 7 Human Oncology and Pathogenesis Program and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. 8 Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA. 9 Oncoematologia Pediatrica, Azienda Policlinico OVE, 95125, Catania, Italy. Correspondence and requests for materials should be addressed to S.A.A. (email: [email protected]). NATURE COMMUNICATIONS | 5:3469 | DOI: 10.1038/ncomms4469 | www.nature.com/naturecommunications 1 & 2014 Macmillan Publishers Limited. All rights reserved. ARTICLE NATURE COMMUNICATIONS | DOI: 10.1038/ncomms4469 elapse occurs in 15–20% of paediatric ALL and 50% of regulators. However, thus far, no published study has addressed adult ALL patients. Compared to de novo leukaemia, the mutational frequency of epigenetic regulators at ALL relapse, Rrelapsed leukaemia is chemoresistant and long-term and whether they are frequently enriched at relapse compared to survival is poor; however, the genetic basis for this is not well at diagnosis. understood. Studies of matched diagnosis and relapse ALL Here, we sequence matched sets of diagnosis–remission– samples by SNP arrays demonstrated that 92% of relapsed ALL relapse samples from paediatric ALL patients, and find a had DNA copy number variant (CNV) changes from diagnosis. significant enrichment of mutations in epigenetic regulators at Surprisingly, over half of relapses are missing CNVs present in relapse, including the H3K36 trimethyltransferase SETD2. We the predominant clone at diagnosis and appear to have derived conclude that these mutations are likely involved in chemother- from a minor subclone in many cases1. Targeting alterations that apy resistance and deserve further study to define their role in the are frequently gained at relapse is therefore a rational therapeutic prognosis and treatment of ALL. strategy, as these lesions are likely associated with chemotherapy resistance and clonal survival. Unfortunately, most CNV alterations gained at ALL relapse are difficult to target, such as Results CDKN2A or ETV6 deletion. Somatic mutations in epigenetic regulators in de novo ALL.To Alterations in epigenetic regulators have recently been study this, we performed custom exon-hybrid capture and Illu- identified in genome and exome sequencing studies of che- mina sequencing of 472 known and putative epigenetic regulators motherapy resistant, very high-risk subsets of de novo ALL. For and frequently mutated genes in leukaemia (Supplementary example, 48% of early T-cell precursor (ETP) ALL2 and 60% of Table 1) on matched diagnostic-remission samples from 60 hypodiploid ALL3 have somatic mutations in genes encoding paediatric B-ALL patients, and matched relapse samples from 30 epigenetic regulators. In addition, loss-of-function mutations of those patients that relapsed. Patients in this cohort were those in the histone acetyltransferase CREBBP have also been described with paediatric ALL (primarily B cell), with a range of cytoge- in diagnostic samples from ALL patients who relapse, and in netics and risk groups (Supplementary Table 2). In this cohort, samples from relapsed patients4. As the enzymatic activities of relapsed patients had the bone marrow as a site of relapse, with CREBBP are directly opposed by histone deacetylases, this over 60% marrow involvement. 70% of patients had an identified provided one possible rationale for why histone deacetylase somatic mutation at diagnosis and/or relapse (Fig. 1). inhibitors have activity in ALL. These studies suggest a broader Considering only samples from the time of diagnosis, somatic paradigm in that mutations in epigenetic regulators may be variants in epigenetic regulators were found in 25% of 60 B-ALL associated with therapy resistance and can be targeted indirectly samples (Fig. 2), which was similar to de novo T-ALL patients5. through inhibition of the enzymatic activity of opposing In contrast, 50% of B-ALL samples harboured a mutation in a TCALL044 TCALL026 TCALL031 TCALL033 TCALL041 TCALL059 TCALL060 TCALL043 TCALL013 TCALL037 TCALL038 TCALL003 TCALL010 TCALL030 TCALL046 TCALL034 TCALL006 TCALL051 TCALL048 TCALL004 TCALL011 TCALL047 TCALL020 TCALL053 TCALL001 TCALL005 TCALL007 TCALL012 TCALL014 TCALL050 TCALL017 TCALL022 TCALL008 TCALL024 TCALL054 TCALL057 TCALL015 TCALL040 TCALL039 TCALL028 TCALL025 TCALL058 TCALL027 TCALL056 TCALL002 TCALL042 TCALL049 TCALL016 TCALL018 TCALL019 TCALL021 TCALL023 TCALL029 TCALL036 TCALL009 TCALL055 TCALL035 TCALL045 TCALL052 TCALL032 KRAS Signaling S NNNNNNNNNN N NRAS Signaling NNNNNNNNNN N CREBBP Acetyltransferase N N N N X S NN SETD2 Methyltransferase X X X X FLT3 Signaling NNN N JAK2 Signaling NNN KDM6A Demethylase NN MSH6 DNA repair X N MLL2 Methyltransferase X X IKZF1 Transcription factor XX PHF3 PHD domain N BRPF1 Acetyltransferase N ATF7IP Binds SETDB1 X BRD8 Bromodomain protein S JHDM1D Demethylase S JMJD1C Demethylase N KDM5C Demethylase S SETDB1 Methyltransferase N EZH2 Methyltransferase (PcG) N BPTF Remodeling N CHD1 Remodeling X CHD7 Remodeling N CHD9 Remodeling N MTA1 Remodeling N SRCAP Remodeling N ZNF541 Remodeling N ETV6 Transcription factor X RUNX1 Transcription factor X TP53 Tumor suppressor N HUWE1 Ubiquitin ligase N Risk group BCR-ABL MLL HYPO iAMP21 ETV6/RUNX1 HYPER Frameshift or nonsenseMissense Splice site Relapsed Did not relapse Very high risk High risk Medium risk Low/standard risk Figure 1 | Targeted hybrid capture sequencing identified somatic mutations in 70% of B-ALL patients. Matched tumour-remission samples from 60 paediatric B-ALLs were sequenced with targeted hybrid capture and somatic mutations in any tumour sample were identified. Genes on the left are organized by mutational frequency. The type of alteration is identified for each mutation as frameshift/stop, missense or splice site mutation. MLL, MLL rearranged; HYPO, hypodiploidy; iAMP21, intrachromosomal amplification of chromosome 21; HYPER, hyperdiploidy. 2 NATURE COMMUNICATIONS | 5:3469 | DOI: 10.1038/ncomms4469 | www.nature.com/naturecommunications & 2014 Macmillan Publishers Limited. All rights reserved. NATURE COMMUNICATIONS | DOI: 10.1038/ncomms4469 ARTICLE TCALL046 TCALL035 TCALL051 TCALL005 TCALL032 TCALL024 TCALL001 TCALL021 TCALL045 TCALL059 TCALL056 TCALL015 TCALL058 TCALL006 TCALL038 TCALL049 TCALL054 TCALL050 TCALL057 TCALL042 TCALL043 TCALL055 TCALL040 TCALL034 TCALL047 TCALL011 TCALL033 TCALL041 TCALL027 TCALL017 TCALL022 TCALL002 TCALL008 TCALL010 TCALL004 TCALL007 TCALL016 TCALL019 TCALL023 TCALL029 TCALL031 TCALL020 TCALL052 TCALL044 TCALL025 TCALL053 TCALL028 TCALL037 TCALL048 TCALL039 TCALL036 TCALL060 TCALL013 TCALL003 TCALL030 TCALL012 TCALL014 TCALL018 TCALL026 TCALL009 SETD2 Methyltransferase CREBBP Acetyltransferase KDM6A Demethylase KDM5C Demethylase BRD8 Bromodomain protein SETDB1 Methyltransferase MTA1 Remodeling Epigenetic regulators MSH6 DNA repair ATF7IP Binds SETDB1 PHF3 PHD domain KRAS Signaling NRAS Signaling FLT3 Signaling Signaling JAK2 Signaling IKZF1 Transcription factor ETV6 Transcription factor Other RUNX1 Transcription factor HUWE1 Ubiquitin ligase Risk group BCR-ABL MLL HYPO iAMP21 ETV6/RUNX1 HYPER Frameshift or nonsense Missense Splice site Relapsed Did not relapse Very high risk High risk Medium risk Low/standard risk Figure 2 | Mutations in epigenetic regulators occur in 25% of B-ALL patients at diagnosis, including SETD2. Matched diagnosis and remission sample pairs from 60 paediatric B-ALL patients were baited with target hybrid capture, Illumina sequenced and somatic mutations were identified. Patients are organized by those that eventually relapsed (on the left), and those that did not (on the right). Final risk category and molecular
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