Cryptic KMT2A::AFDN Fusion Due to AFDN Insertion into KMT2A in a Patient with Acute Monoblastic Leukemia

Authors

Qing Wei
Gokce A Toruner
Beenu Thakral
Keyur P Patel
Naveen Pemmaraju
Sa A Wang
Rashmi Kanagal-Shamanna
Guilin Tang
Ghayas C Issa
Sanam Loghavi
L Jeffrey Medeiros
Courtney DiNardo

Publication Date

3-7-2025

Journal

Genes

Abstract

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' 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' 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' 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.

Keywords

Humans, Female, Myeloid-Lymphoid Leukemia Protein, Histone-Lysine N-Methyltransferase, Oncogene Proteins, Fusion, Leukemia, Monocytic, Acute, In Situ Hybridization, Fluorescence, Translocation, Genetic, Young Adult, Chromosomes, Human, Pair 11, Adult, Leukemia, Myeloid, Acute, KMT2A::AFDN rearrangement, fluorescence in situ hybridization (FISH), RNA fusion panel, optical genome mapping, acute monocytic leukemia

DOI

10.3390/genes16030317

PMID

40149468

PMCID

PMC11942050

PubMedCentral® Posted Date

3-7-2025

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes