Targeting DLK1 improves survival in patient-derived xenograft models of myeloid leukemia associated with Down syndrome

Abstract Myeloid leukemia associated with Down syndrome (ML-DS) is a rare pediatric cancer. Current standard-of-care includes cytotoxic chemotherapy. 10-20% of patients develop relapsed leukemia or have refractory disease. These patients have a 3-year event-free survival less than 21%. Novel therapy options are needed to improve survival in these patients with relapsed or refractory disease. Our transcriptome analysis to identify transmembrane proteins that are overexpressed in ML-DS compared to normal bone marrow specimens revealed DLK1 as one of the topmost modulated targets. We show that DLK1 knockout in ML-DS cells significantly reduced proliferation in vitro and delayed engraftment in vivo . Furthermore, targeting DLK1 via antibody drug conjugates significantly prolonged survival compared to control isotype antibody drug conjugate in patient-derived xenograft models of refractory ML-DS. Taken together, targeting DLK1 may be a novel treatment option for refractory ML-DS patients. Key Points We identified DLK1 as a novel target differentially expressed in myeloid leukemia associated with Down syndrome (ML-DS). DLK1-targeted antibody drug conjugate was effective in curbing leukemia progression in patient-derived xenograft models of refractory ML-DS