Single cell analysis reveals molecular traits of pediatric lymphoma resistant subclones

The cause of refractory/relapse (R/R) in pediatric lymphoma is unclear. We hypothesized that a stem-like, chemoresistance lymphoma subclone may contribute to R/R. Combining single cell RNA sequencing (scRNA-seq) and immune receptor sequencing (scVDJ-seq) on freshly acquired pediatric non-Hodgkin lymphoma (pNHL n=10), Hodgkin lymphoma (pHL n=5), and 10 reactive lymph nodes from adults or children (a/pReLy), we discovered pediatric-specific progenitor-like lymphocytes, whose cellular program was enriched in pNHL subclones emerging late during clonal evolution, accompanied by loss of immune receptor expression. R-CHOP target gene expression indicated that these subclones may escape first-line treatment, and suggested MSI2, an RNA binding protein, as a potential target. In pHL, the progenitor-like program was found in the tumor microenvironment (TME) but not Hodgkin cells which, during relapse, were myeloid-like and accompanied by CD74highCCL5+ CD8 T cells. In summary, we discovered R/R associated lymphoma subclones in pediatric lymphoma and potential ways to eradicate them.