{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T20:21:25Z","timestamp":1780518085004,"version":"3.54.1"},"reference-count":16,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T00:00:00Z","timestamp":1741305600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: KMT2A rearrangements occur in ~10% of acute myeloid leukemia (AML) cases and are critical for classification, risk stratification, and use of targeted therapy. However, insertions involving the KMT2A gene can evade detection using chromosomal analysis and\/or fluorescence in situ hybridization (FISH). Methods: We present a case of a 22-year-old woman with acute monoblastic leukemia harboring a cryptic KMT2A::AFDN fusion identified by RNA sequencing. Initial FISH showed a 3\u2032 KMT2A deletion, while conventional karyotyping and the automated bioinformatic pipeline for optical genome mapping (OGM) did not identify the canonical translocation. Results: To resolve these discrepancies, metaphase KMT2A FISH (break-apart fusion probe) was performed to assess whether KMT2A was translocated to another chromosome. However, the results did not support this possibility. As the fusion signal remained on the normal chromosome 11, with the 5\u2032 KMT2A signal localized to the derivative chromosome 11. A subsequent manual review of the OGM data revealed a cryptic ~300 kb insertion of AFDN into the 3\u2032 region of KMT2A, reconciling the discrepancies between chromosomal analysis, FISH, and RNA fusion results. Conclusions: This case highlights the importance of integrating multiple testing modalities with expert review when there is a discrepancy. Our findings emphasize the need for a comprehensive approach to genomic assessment to enhance diagnostic accuracy and guide therapeutic decision-making.<\/jats:p>","DOI":"10.3390\/genes16030317","type":"journal-article","created":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T07:05:46Z","timestamp":1741331146000},"page":"317","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cryptic KMT2A::AFDN Fusion Due to AFDN Insertion into KMT2A in a Patient with Acute Monoblastic Leukemia"],"prefix":"10.3390","volume":"16","author":[{"given":"Qing","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Avenue, Z5.5048, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5305-6337","authenticated-orcid":false,"given":"Gokce A.","family":"Toruner","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Avenue, Z5.5048, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5140-3633","authenticated-orcid":false,"given":"Beenu","family":"Thakral","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Avenue, Z5.5048, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keyur P.","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Avenue, Z5.5048, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1670-6513","authenticated-orcid":false,"given":"Naveen","family":"Pemmaraju","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Avenue, Z5.5048, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sa A.","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Avenue, Z5.5048, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7829-5249","authenticated-orcid":false,"given":"Rashmi","family":"Kanagal-Shamanna","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Avenue, Z5.5048, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9482-4806","authenticated-orcid":false,"given":"Guilin","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Avenue, Z5.5048, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4339-8683","authenticated-orcid":false,"given":"Ghayas C.","family":"Issa","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Avenue, Z5.5048, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8980-3202","authenticated-orcid":false,"given":"Sanam","family":"Loghavi","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Avenue, Z5.5048, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6577-8006","authenticated-orcid":false,"given":"L Jeffrey","family":"Medeiros","sequence":"additional","affiliation":[{"name":"Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Avenue, Z5.5048, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9003-0390","authenticated-orcid":false,"given":"Courtney","family":"DiNardo","sequence":"additional","affiliation":[{"name":"Department of Leukemia, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Avenue, Z5.5048, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1038\/s41375-023-01877-1","article-title":"The KMT2A recombinome of acute leukemias in 2023","volume":"37","author":"Meyer","year":"2023","journal-title":"Leukemia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4532","DOI":"10.1182\/blood.V90.11.4532","article-title":"Adult patients with de novo acute myeloid leukemia and t(9; 11)(p22; q23) have a superior outcome to patients with other translocations involving band 11q23: A cancer and leukemia group B study","volume":"90","author":"Heinonen","year":"1997","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1097\/MOH.0000000000000245","article-title":"Deregulation of the HOXA9\/MEIS1 axis in acute leukemia","volume":"23","author":"Collins","year":"2016","journal-title":"Curr. Opin. Hematol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1182\/blood-2009-04-215152","article-title":"Novel prognostic subgroups in childhood 11q23\/MLL-rearranged acute myeloid leukemia: Results of an international retrospective study","volume":"114","author":"Balgobind","year":"2009","journal-title":"Blood"},{"key":"ref_5","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_6","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1038\/sj.leu.2401013","article-title":"The t(6;11)(q27;q23) translocation in acute leukemia: A laboratory and clinical study of 30 cases","volume":"12","author":"Martineau","year":"1998","journal-title":"Leukemia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2306","DOI":"10.1038\/s41375-019-0451-7","article-title":"Human MLL\/KMT2A gene exhibits a second breakpoint cluster region for recurrent MLL-USP2 fusions","volume":"33","author":"Meyer","year":"2019","journal-title":"Leukemia"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.cancergen.2023.07.003","article-title":"Cryptic KMT2A\/MLLT10 fusion detected by next-generation sequencing in a case of pediatric acute megakaryoblastic leukemia","volume":"276\u2013277","author":"Kim","year":"2023","journal-title":"Cancer Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e95","DOI":"10.1093\/labmed\/lmab109","article-title":"Detection of a Cryptic KMT2A\/AFDN Gene Fusion [ins(6;11)(q27;q23q23)] in a Pediatric Patient with Newly Diagnosed Acute Myeloid Leukemia","volume":"53","author":"Berg","year":"2022","journal-title":"Lab Med."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Wei, Q., Hu, S., Xu, J., Loghavi, S., Daver, N., Toruner, G.A., Wang, W., Medeiros, L.J., and Tang, G. (2024). Detection of KMT2A Partial Tandem Duplication by Optical Genome Mapping in Myeloid Neoplasms: Associated Cytogenetics, Gene Mutations, Treatment Responses, and Patient Outcomes. Cancers, 16.","DOI":"10.3390\/cancers16244193"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S0165-4608(03)00158-4","article-title":"Detection of cryptic MLL insertions using a commercial dual-color fluorescence in situ hybridization probe","volume":"147","author":"Dyson","year":"2003","journal-title":"Cancer Genet. Cytogenet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2496","DOI":"10.1182\/blood.V87.6.2496.bloodjournal8762496","article-title":"Incidence and characterization of MLL gene (11q23) rearrangements in acute myeloid leukemia M1 and M5","volume":"87","author":"Poirel","year":"1996","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1038\/sj.leu.2401012","article-title":"Hematologic malignancies with t(4;11)(q21;q23)\u2014A cytogenetic, morphologic, immunophenotypic and clinical study of 183 cases","volume":"12","author":"Johansson","year":"1998","journal-title":"Leukemia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.cancergencyto.2008.01.016","article-title":"MLL insertion with MLL-MLLT3 gene fusion in acute leukemia: Case report and review of the literature","volume":"183","author":"Soler","year":"2008","journal-title":"Cancer Genet. Cytogenet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1038\/s41375-023-02102-9","article-title":"Panel-based RNA fusion sequencing improves diagnostics of pediatric acute myeloid leukemia","volume":"38","author":"Hoffmeister","year":"2024","journal-title":"Leukemia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1002\/cyto.b.22051","article-title":"Comprehensive immunophenotypic study of acute myeloid leukemia with KMT2A (MLL) rearrangement in adults: A single-institution experience","volume":"102","author":"Konoplev","year":"2022","journal-title":"Cytom. B Clin. Cytom."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/3\/317\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:48:52Z","timestamp":1760028532000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/16\/3\/317"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,7]]},"references-count":16,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["genes16030317"],"URL":"https:\/\/doi.org\/10.3390\/genes16030317","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,7]]}}}