LAMPs (lysosome associated membrane proteins) represent a family of glycosylated proteins present predominantly on the membrane of lysosomes whose expression can vary among different tissues, suggesting a separation of functions. LAMP5 is expressed highly and specifically in MLL-r leukemia. LAMP5 is a direct target of the oncogenic MLL-fusion protein. LAMP5 depletion significantly inhibited leukemia cell growth in vitro and in vivo. Functional studies showed that LAMP-5 is a novel modulator of innateimmune pathways in MLL-r leukemias. Downregulation of LAMP5 led to inhibition of NF-κB signaling and increased activation of type-1 interferon signaling downstream of Toll-like Receptor/Interleukin 1 Receptor activation.