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.