Three-Way Chromosomal Translocation Involving KMT2A::MLLT3 in AML: A Case Report and Genomic Characterization

Complex chromosomal translocations can obscure the identification of pathogenic rearrangements involving KMT2A in acute myeloid leukemia (AML).

We report a 20-year-old female with AML harboring a novel three-way translocation, t(9;11;19)(p21;q23;q13.1), resulting in a KMT2A::MLLT3 fusion. The patient presented with gingival swelling, oral ulcers, anemia, thrombocytopenia, leukocytosis, and 95% peripheral blasts. Flow cytometry showed blasts expressing CD11c, CD13, CD33, CD38, CD64, CD117, and HLA-DR. Conventional cytogenetics and KMT2A break-apart FISH confirmed rearrangement in nearly all cells. Whole-genome sequencing resolved the structural architecture, identifying a BND-type event fusing KMT2A exon 8 to MLLT3 exon 6, along with a non-functional head-to-head involvement of TBCB. RNA sequencing confirmed the pathogenic KMT2A::MLLT3 transcript without evidence of TBCB fusion or overexpression. Additional NRAS and KRAS mutations were detected. The patient achieved complete remission following induction and consolidation chemotherapy but relapsed one year later. She subsequently underwent allogeneic stem cell transplantation, relapsed four months post-transplant, and died two years after diagnosis.

This case represents an exceptionally rare instance of KMT2A::MLLT3 generated through a three-way complex translocation and highlights the utility of whole-genome and transcriptome sequencing in clarifying rearrangement topology. The aggressive clinical course raises important questions about the prognostic implications of structural complexity and cooperating RAS mutations in KMT2A-rearranged AML.