A Case of Concordant Twins with Infant ALL and Discordant Clinical Outcome – Part I: the genetic basis – identification of DSC2 as a gene with prognostic impact in infant MLL-rearranged ALL

Infant acute lymphoblastic leukemia (ALL) is associated with an unfavorable prognosis due to a high proportion of early relapses. We report on a pair of monozygotic twin sisters diagnosed with ALL (MLL-ENL fusion) in early infancy. Despite good initial treatment responses in both twins, one sister developed very early relapse (Twin A) and succumbed to the disease. The other sister went into continuous complete remission (Twin B) and is alive after 9 years. We performed exome sequencing experiments to identify additional diverging mutations in the twins that may be connected to the different clinical outcomes. Results obtained were further complemented by sequencing analyses of xenografted twin leukemias from different disease time points providing insights into clonal evolution in this twin model of infant leukemia. Apart from an overall paucity of mutations, genetic alterations predicted to be relevant were detected only in leukemic cells of the survivor, Twin B. In particular, we show evidence for a heterozygous desmocollin 2 (DSC2) mutation which is absent in Twin A. Notably, high gene expression of DSC2 in a cohort of infant ALL patients harboring MLL-ENL and MLL-AF9 fusions conferred a poor prognosis characterized by a significantly increased relapse rate. Our data suggest that high levels of DSC2 expression in residual cells may be a pathogenic mechanism in relapsing infant ALL.