MLL-rearranged acute lymphoblastic leukemia (ALL) represents a highly aggressive and chemoresistant type of hematologic malignancy that typically affects infants (i.e. children <1 year of age). Strikingly, the event-free survival (EFS) chances for these patients currently are at best 30-40%. A considerable subset of these patients also present with leukemic infiltration of the central nervous system (CNS). Despite the fact that current treatment protocols for MLL-rearranged infant ALL do include CNS-directed therapeutics, CNS infiltration remains an adverse prognostic factor among these patients already burdened with a highly dismal prognosis. Within this project, we aim to pre-clinically identify druggable molecular determinants of CNS infiltration using an in vitro blood-brain-barrier (BBB) mimicking model system and an in vivo xenograft mouse model for CNS infiltrating MLL-rearranged ALL. Together these approaches will help us to develop therapeutic strategies to increase the prognosis for MLL-rearranged infant ALL patients with CNS involvement.