journal contribution posted on 2023-03-31, 21:40 authored by Wen-Tao Wang, Cai Han, Yu-Meng Sun, Zhen-Hua Chen, Ke Fang, Wei Huang, Lin-Yu Sun, Zhan-Cheng Zeng, Xue-Qun Luo, Yue-Qin Chen
Supplementary Figures including Fig. S1. Expression of LAMP5 in leukemia subtypesï¼ŒFig. S2. Knockdown of LAMP5 in MLL leukemia cellsï¼ŒFig. S3. LAMP5 regulated the apoptosis of MLL leukemia cellsï¼ŒFig. S4. LAMP5 regulates MLL leukemia progression in vivoï¼ŒFig. S5. LAMP5 regulates autophagy in MLL leukemia cellsï¼ŒFig. S6. LAMP5 was the target of DOT1L and susceptibility to DOT1L inhibitorï¼ŒFig. S7. Combination of DOT1L inhibitor and LAMP5-Knockdown suppresses leukemia progression
National Key R&D Program of China
National Natural Science Foundation of China
ARTICLE ABSTRACTDespite 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 LAMP5 expression and evaluate its clinical value. We then performed in vitro and in vivo experiments to investigate the functional relevance of LAMP5 in MLL leukemia progression or maintenance.
LAMP5 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 LAMP5 is a direct target of the H3K79 histone methyltransferase DOT1L. Downregulating LAMP5 with a DOT1L inhibitor enhanced the selective autophagic degradation of MLL oncoproteins and extended survival in vivo; 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 LAMP5 as a therapeutic target for MLL leukemia.