DISCUSSION
We have described an intractable case of pediatric DLBCL withKMT2A rearrangement. The patient showed histological similarities with DLBCL; however, she exhibited disease relapse with leukemic conversion soon after chemotherapy against mature B-cell lymphoma. She was resistant to the salvage chemotherapy.
The KMT2A -MLLT3 fusion in BM motivated us to further investigate the biological features of the cancer. RNA-seq did not identify other fusions associated with DLBCL, but revealed the overexpression of genes associated with KMT2A -rearranged leukemia, such as MEIS1 .17 Moreover, the patient formed a part of the KMT2A -rearranged ALL cluster in the t-SNE plot. These results suggested that KMT2A -rearranged DLBCL shares biological features with KMT2A -rearranged leukemia, thereby resulting in resistance to treatment.
In contrast, the posterior HOXA cluster, upregulated inKMT2A -rearranged leukemia, was not overexpressed.17 Posterior HOXA is maximally expressed at the progenitor stage;18 therefore, the low expression of posterior HOXA in our patient could be attributed to the maturity of lymphoma cells (confirmed by flow cytometry and RNA-seq). Although KMT2A rearrangement is assumed to occur in early B-cell precursors, additional genetic aberrations, such as mutations in RAS pathway genes or tyrosine kinase domain mutations or ITD in FLT3 , are pivotal for leukemogenesis.13,14,19,20 KMT2A -rearranged B-lineage ALL mainly includes pro-B-ALL, the most immature phenotype of precursor B-cell ALL;19 whereas someKMT2A -rearranged lymphoblastic lymphoma has a mature B-cell phenotype.4,6 Thus, the stage of differentiation in which aberrations other than KMT2A rearrangement occur might determine disease phenotype, i.e., development of ALL or lymphoma.
KMT2A -rearranged DLBCL has been reported in two adults and one child.9,10 The adults maintained remission after R-CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone, and rituximab).9 The pediatric case demonstrated poor response to mature B-cell lymphoma-specific chemotherapy and was in remission after high-dose cytarabine and oral maintenance chemotherapy with 6-mercaptopurine and methotrexate.10 This difference in therapeutic response between the adult and pediatric cases, including our patient, may be attributed to differences in their genetic background. However, previous reports have not identified genetic alterations other thanKMT2A rearrangement.
In conclusion, although further investigation is warranted, there might be similarities between the characteristics of KMT2A -rearranged DLBCL and leukemia at the molecular level.