{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T20:16:52Z","timestamp":1790108212703,"version":"4.0.1"},"reference-count":40,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001411","name":"Indian Council of Medical Research","doi-asserted-by":"crossref","award":["5\/13\/13\/2020\/NCD-III"],"award-info":[{"award-number":["5\/13\/13\/2020\/NCD-III"]}],"id":[{"id":"10.13039\/501100001411","id-type":"DOI","asserted-by":"crossref"}]},{"award":["5\/13\/13\/2020\/NCD-III"],"award-info":[{"award-number":["5\/13\/13\/2020\/NCD-III"]}],"id":[{"id":"https:\/\/ror.org\/0492wrx28","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Epigenomes"],"abstract":"<jats:p>Background\/Objectives: Juvenile myelomonocytic leukemia (JMML) is a rare, highly aggressive form of pediatric myelodysplastic\/myeloproliferative neoplasm characterized by molecular heterogeneity and constitutive activation of the RAS signaling pathway. This study aimed to characterize the mutational landscape, driver genes, mutational signatures, functional pathways, and therapeutic potential of mutated epigenetic regulator genes in JMML. Methods: Tumor and matched buccal swab samples were collected from 35 JMML patients, and whole-exome sequencing was performed. Somatic variants were called with GATK-Mutect2 and annotated with ANNOVAR. maftools and OncodriveCLUST were used for mutational profiling, co-occurrence analysis, driver gene identification, and protein domain mapping. Drug\u2013gene interactions were explored using DGIdb, mutational signatures for genes were characterized by MutationalPatterns, and functional enrichment analysis was performed by the clusterProfiler package. Results: A total of 28 variants were detected in epigenetic regulator genes, with missense mutations being the most common class of variants and a C&gt;T nucleotide substitution pattern being the most frequent. EP300, SETD2, and DNMT3B were the genes most frequently altered, with 8.57% of cases each, followed by ASXL1, BCORL1, ATRX, KMT2A, and TET2 (5.71% each). Driver gene analysis identified ASXL1 as the top candidate driver gene, followed by BCORL1, EP300, and SETD2. Functional enrichment analysis revealed a high number of genes involved in chromatin organization, histone modification, transcriptional regulation, and oncogenic signaling pathways. The mutational signatures identified were SBS5-like, which are dominated by C&gt;T and T&gt;C transitions, indicating endogenous mutational processes. Analysis of drug\u2013gene interactions revealed KMT2A, EP300, and ATRX as the most interconnected and potentially actionable therapeutic targets. Conclusions: This study provides a comprehensive characterization of epigenetic regulator gene alterations in JMML and highlights the importance of epigenetic dysregulation in disease pathogenesis.<\/jats:p>","DOI":"10.3390\/epigenomes10030056","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T07:58:23Z","timestamp":1787126303000},"page":"56","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genomic Characterization of Epigenetic Regulator Gene Alterations in Juvenile Myelomonocytic Leukemia Through Whole-Exome Sequencing"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3904-7343","authenticated-orcid":false,"given":"Harsh","family":"Goel","sequence":"first","affiliation":[{"name":"Laboratory Oncology Unit, Dr. B.R.A. Institute of Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi Kumar","family":"Majhi","sequence":"additional","affiliation":[{"name":"Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jagdish Prasad","family":"Meena","sequence":"additional","affiliation":[{"name":"Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0238-8702","authenticated-orcid":false,"given":"Anita","family":"Chopra","sequence":"additional","affiliation":[{"name":"Laboratory Oncology Unit, Dr. B.R.A. Institute of Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameer","family":"Bakhshi","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Dr. B.R.A. Institute of Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8981-2237","authenticated-orcid":false,"given":"Lata","family":"Singh","sequence":"additional","affiliation":[{"name":"Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachna","family":"Seth","sequence":"additional","affiliation":[{"name":"Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2357-976X","authenticated-orcid":false,"given":"Pranay","family":"Tanwar","sequence":"additional","affiliation":[{"name":"Laboratory Oncology Unit, Dr. B.R.A. Institute of Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3730-8944","authenticated-orcid":false,"given":"Aditya Kumar","family":"Gupta","sequence":"additional","affiliation":[{"name":"Division of Pediatric Oncology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110029, India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1182\/blood-2014-08-550483","article-title":"How I treat juvenile myelomonocytic leukemia","volume":"125","author":"Locatelli","year":"2015","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1182\/blood-2018-11-844688","article-title":"Juvenile myelomonocytic leukemia: Who\u2019s the driver at the wheel?","volume":"133","author":"Niemeyer","year":"2019","journal-title":"Blood"},{"key":"ref_3","first-page":"1569","article-title":"Childhood myelodysplastic syndrome in Denmark: Incidence and predisposing conditions","volume":"9","author":"Hasle","year":"1995","journal-title":"Leukemia"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1038\/s41375-022-01613-1","article-title":"The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic\/Dendritic Neoplasms","volume":"36","author":"Khoury","year":"2022","journal-title":"Leukemia"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1182\/blood.2022015850","article-title":"International consensus classification of myeloid neoplasms and acute leukemias: Integrating morphology, genomics, and clinical features","volume":"140","author":"Arber","year":"2022","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1182\/blood.V77.5.925.925","article-title":"Selective hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors","volume":"77","author":"Emanuel","year":"1991","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1038\/s41375-023-01818-y","article-title":"Juvenile myelomonocytic leukemia; moving forward","volume":"37","author":"Elghetany","year":"2023","journal-title":"Leukemia"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.3324\/haematol.2014.114595","article-title":"RAS diseases in children","volume":"99","author":"Niemeyer","year":"2014","journal-title":"Haematologica"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1038\/ng.3400","article-title":"The genomic landscape of juvenile myelomonocytic leukemia","volume":"47","author":"Stieglitz","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_10","first-page":"3534","article-title":"Chronic myelomonocytic leukemia in childhood: A retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS)","volume":"89","author":"Niemeyer","year":"1997","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1182\/blood-2004-05-1944","article-title":"Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): Results of the EWOG-MDS\/EBMT trial","volume":"105","author":"Locatelli","year":"2005","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1136\/jmedgenet-2014-102611","article-title":"Juvenile myelomonocytic leukaemia and Noonan syndrome","volume":"51","author":"Strullu","year":"2014","journal-title":"J. Med. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1038\/ng.3420","article-title":"Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and theho","volume":"47","author":"Caye","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1038\/ng.2698","article-title":"Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia","volume":"45","author":"Sakaguchi","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"28914","DOI":"10.18632\/oncotarget.8016","article-title":"Mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia: A report from the Italian AIEOP study group","volume":"7","author":"Bresolin","year":"2016","journal-title":"Oncotarget"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1038\/s41375-019-0662-y","article-title":"Despite mutation acquisition in hematopoietic stem cells, JMML-propagating cells are not always restricted to this compartment","volume":"34","author":"Caye","year":"2020","journal-title":"Leukemia"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1038\/nrc3895","article-title":"DNMT3A in haematological malignancies","volume":"15","author":"Yang","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2126","DOI":"10.1038\/s41467-017-02177-w","article-title":"RAS-pathway mutation patterns define epigenetic subclasses in juvenile myelomonocytic leukemia","volume":"8","author":"Lipka","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1182\/blood-2017-07-798157","article-title":"Integrated molecular profiling of juvenile myelomonocytic leukemia","volume":"131","author":"Murakami","year":"2018","journal-title":"Blood"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.1038\/s41467-017-02178-9","article-title":"Genome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia","volume":"8","author":"Stieglitz","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1038\/s41375-021-01479-9","article-title":"Molecular characterization of the histone acetyltransferase CREBBP\/EP300 genes in myeloid neoplasia","volume":"36","author":"Kongkiatkamon","year":"2022","journal-title":"Leukemia"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e18","DOI":"10.1016\/j.leukres.2010.09.024","article-title":"Novel variant form of t(11;22)(q23;q13)\/MLL-EP300 fusion transcript in the evolution of an acute myeloid leukemia with myelodysplasia-related changes","volume":"35","author":"Duhoux","year":"2011","journal-title":"Leuk. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2576","DOI":"10.1182\/blood-2017-10-811927","article-title":"SETD2: A complex role in blood malignancy","volume":"130","author":"Licht","year":"2017","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1182\/blood.2019001963","article-title":"SETD2 deficiency accelerates MDS-associated leukemogenesis via S100a9 in NHD13 mice and predicts poor prognosis in MDS","volume":"135","author":"Chen","year":"2020","journal-title":"Blood"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1111\/bjh.70060","article-title":"Co-operative epigenetic remodelling by Setd2 deficiency and Kras mutation drives juvenile myelomonocytic leukaemia development and MEK inhibitor sensitivity","volume":"207","author":"Munyurangabo","year":"2025","journal-title":"Br. J. Haematol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4871","DOI":"10.1182\/blood-2010-08-298968","article-title":"Aberrant DNA methylation characterizes juvenile myelomonocytic leukemia with poor outcome","volume":"117","author":"Poetsch","year":"2011","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1158\/1078-0432.CCR-20-3184","article-title":"International Consensus Definition of DNA Methylation Subgroups in Juvenile Myelomonocytic Leukemia","volume":"27","author":"Meyer","year":"2021","journal-title":"Clin. Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1111\/ijlh.13680","article-title":"Mutational landscape of Juvenile Myelomonocytic Leukemia (JMML)-A real-world context","volume":"43","author":"Nathany","year":"2021","journal-title":"Int. J. Lab. Hematol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"553","DOI":"10.5001\/omj.2019.99","article-title":"KMT2A-MLLT3 AML Masquerading as JMML may Disguise Fatal Leukemia","volume":"34","author":"Saad","year":"2019","journal-title":"Oman Med. J."},{"key":"ref_30","first-page":"7151394","article-title":"Pitfalls in Diagnosis: JMML versus KMT2A Rearranged Juvenile AML","volume":"2024","author":"Vanheeswijck","year":"2024","journal-title":"Case Rep. Hematol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/j.1365-2141.2010.08196.x","article-title":"Spectrum of molecular defects in juvenile myelomonocytic leukaemia includes ASXL1 mutations","volume":"150","author":"Sugimoto","year":"2010","journal-title":"Br. J. Haematol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1038\/nature09586","article-title":"Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2","volume":"468","author":"Ko","year":"2010","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.ccr.2012.06.032","article-title":"ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression","volume":"22","author":"Adli","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Spisak, N., de Manuel, M., Milligan, W., Sella, G., and Przeworski, M. (2023). Disentangling sources of clock-like mutations in germline and soma. bioRxiv, Update in PLoS Biol.\u00a02024,\u00a022,\u00a0e3002678. https:\/\/doi.org\/10.1371\/journal.pbio.3002678.","DOI":"10.1371\/journal.pbio.3002678"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1038\/s41586-023-05812-3","article-title":"The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia","volume":"615","author":"Issa","year":"2023","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Goel, H., Pandey, A.K., Arya, A., Kumar, R., Kumar, R., Makkar, H., Majhi, R.K., Bhattacharya, S., Singh, J., and Divakar, M.K. (2026). Integrated Genomic Profiling of Newly Diagnosed and Relapsed Acute Myeloid Leukemia Identifies Driver Genes, Mutational Signatures, and Therapeutic Targets. Cancers, 18.","DOI":"10.3390\/cancers18101532"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1200\/JCO.24.00826","article-title":"Menin Inhibition with Revumenib for KMT2A-Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT-101)","volume":"43","author":"Issa","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/s41420-024-01940-5","article-title":"The epigenetic regulators EP300\/CREBBP represent promising therapeutic targets in MLL-rearranged acute myeloid leukemia","volume":"10","author":"Wu","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/ng1156","article-title":"Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia","volume":"34","author":"Tartaglia","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2127","DOI":"10.2217\/fon-2020-1244","article-title":"EZH2 inhibition by tazemetostat: Mechanisms of action, safety and efficacy in relapsed\/refractory follicular lymphoma","volume":"17","author":"Julia","year":"2021","journal-title":"Future Oncol."}],"container-title":["Epigenomes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4655\/10\/3\/56\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T04:16:05Z","timestamp":1787285765000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4655\/10\/3\/56"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,19]]},"references-count":40,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["epigenomes10030056"],"URL":"https:\/\/doi.org\/10.3390\/epigenomes10030056","relation":{},"ISSN":["2075-4655"],"issn-type":[{"value":"2075-4655","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,19]]}}}