Activation of the Lysosome-Associated Membrane Protein LAMP5 by DOT1L Serves as a Bodyguard for MLL Fusion Oncoproteins to Evade Degradation in Leukemia.

Abstract

Despite many attempts to understand mixed-lineage leukemia (MLL leukemia), effective therapies for this disease remain limited. We identified a lysosome-associated membrane protein (LAMP) family member, LAMP5, that is specifically and highly expressed in patients with MLL leukemia. The purpose of the study was to demonstrate the functional relevance and clinical value of LAMP5 in the disease. We first recruited a large cohort of leukemia patients to validate <i>LAMP5</i> expression and evaluate its clinical value. We then performed <i>in vitro</i> and <i>in vivo</i> experiments to investigate the functional relevance of <i>LAMP5</i> in MLL leukemia progression or maintenance. <i>LAMP5</i> was validated as being specifically and highly expressed in patients with MLL leukemia and was associated with a poor outcome. Functional studies showed that LAMP5 is a novel autophagic suppressor and protects MLL fusion proteins from autophagic degradation. Specifically targeting LAMP5 significantly promoted degradation of MLL fusion proteins and inhibited MLL leukemia progression in both an animal model and primary cells. We further revealed that <i>LAMP5</i> is a direct target of the H3K79 histone methyltransferase DOT1L. Downregulating <i>LAMP5</i> with a DOT1L inhibitor enhanced the selective autophagic degradation of MLL oncoproteins and extended survival <i>in vivo</i>; this observation was especially significant when combining DOT1L inhibitors with LAMP5 knockdown. This study demonstrates that LAMP5 serves as a "bodyguard" for MLL fusions to evade degradation and is the first to link H3K79 methylation to autophagy regulation, highlighting the potential of <i>LAMP5</i> as a therapeutic target for MLL leukemia.