27. KMT2A-ARHGEF12 fusion in Burkitt-like Lymphoma

      Burkitt lymphoma is an aggressive subtype of non-Hodgkin lymphoma in which a fusion gene IGH-MYC or its variants, IGK-MYC or IGL-MYC, is detected in more than 90% of the cases. Burkitt-like lymphomas share certain histological features with Burkitt lymphoma without MYC-associated fusions. Burkitt-like lymphomas often show chromosome 11 abnormalities. Here we report a Burkitt-like lymphoma with a unique gene fusion caused by a cryptic deletion involving the long arm of chromosome 11. A 16-year-old boy presented to the Children's Hospital of Philadelphia (CHOP) with lower abdominal pain. Radiology exams detected soft tissue masses in the abdomen and pelvis. Biopsy showed medium-sized mononuclear cells with oval nuclei, speckled chromatin, and small amounts of cytoplasm. The cells were positive for CD20, CD10, BCL6, MYC, and Ki67 (> 90%) and negative for CD3, BCL2, and TdT. A presumed diagnosis of Burkitt lymphoma was made. Cytogenetic analysis showed a trisomy 12 with no MYC-associated fusion. Fluorescence in situ hybridization analysis detected a deletion of 3’ part of the KMT2A probe. Targeted RNA sequencing using the CHOP cancer fusion panel identified a KMT2A-ARHGEF12 fusion. A single nucleotide polymorphism microarray detected a 2 Mb heterozygous deletion on chromosome 11 between KMT2A and ARHGEF12, which juxtaposed exon 10 of KMT2A to exon 12 of ARHGEF12. The patient was diagnosed with Stage III/Group B mature B cell Burkitt-like lymphoma, negative for the MYC fusion. The tumor responded effectively to chemotherapy/anti-CD20 antibody-incorporated Burkitt lymphoma therapy at CHOP, and the boy has remained healthy since the completion of the treatment. The KMT2A-ARHGEF12 fusion retains the CXXC domain of KMT2A, which binds nonmethylated CpG-containing DNA and is essential for the oncogenic properties of KMT2A fusion proteins. However, additional studies are needed to illustrate the oncogenic function of this fusion gene and its potential role in Burkitt-like lymphoma.
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