Systematic chemical and molecular profiling of MLL-rearranged infant acute lymphoblastic leukemia reveals efficacy of Romidepsin. Homo sapiens

To address the poor prognosis of MLL-rearranged (MLL-r) infant acute lymphoblastic leukemia (iALL), we generated a panel of MLL-r iALL cell lines from primary patient samples and investigated cytotoxicity to contemporary chemotherapeutics and novel US Food and Drug Administration-approved drugs. Molecular features of cell lines and patient specimens were compared using RNA-sequencing and traditional cytogenetic methods to characterize representation of the primary disease within the in vitro models. High-throughput drug screening revealed variable efficacy of chemotherapeutic agents currently used to treat iALL and identified three novel drug classes with consistent efficacy: proteasome-inhibitors, histone deacetylase-inhibitors and cyclin-dependent kinase-inhibitors. Expression analysis demonstrated that primary samples and cell lines show reproducible expression of genes targeted in our chemical screen including proteasome subunits, histone deacetylase repressor subunits and cyclin-dependent kinases, with the notable exception of growth factor receptor tyrosine kinase encoding genes. The histone deacetylase-inhibitor, romidepsin, enhanced the in vitro activity of a key component of iALL therapy, cytosine arabinoside, and showed single-agent activity in two MLL-r iALL xenograft models. In conclusion, we present a valuable resource for drug discovery, including the first systematic analysis of transcriptome reproducibility in vitro, and have identified romidepsin as a promising therapeutic candidate for MLL-r iALL.