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

Abstract

Purpose: Despite many attempts to understand mixedlineage 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. Experimental Design: 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. Results: 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. Conclusions: 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.

Epigenetic synthetic lethality approaches in cancer therapy

“…Another mechanism research found that LAMP5 is positively correlated with the MLL fusion protein level and LAMP5 can be activated by H3K79me2 as a direct target which is generated by DOT1L. Therefore, inhibition of DOT1L can abolish the inhibition of autophagy by LAMP5 [38]. It was also found that MLL fusion protein levels decreased significantly after treatment with DOT1L inhibitors.…”

Secreted breast tumor interstitial fluid microRNAs and their target genes are associated with triple-negative breast cancer, tumor grade, and immune infiltration

“…Darker color = more miRNAs belonging to this family. Arrows = miRNAs of interest evade degradation[91]. A total of 51 mRNAs and 65 genes were unique to the cluster 1 vs cluster 2 comparison-Additional file 6:…”

The lncRNA LAMP5-AS1 drives leukemia cell stemness by directly modulating DOT1L methyltransferase activity in MLL leukemia

“…MOLM13, THP1, and RS4-11 were cultured in RPMI-1640 medium (HyClone, USA); MV4-11 cells were cultured in IMDM (HyClone), and HEK 293T (ATCC) were cultured in DMEM (Gibco) supplemented with 10% FBS (HyClone) at 37°C in a 5% CO 2 atmosphere. The primary cells were from the patients with MLL leukemia and cultured in IMDM (HyClone) supplemented with 20% FBS [27,28]. Primary CD34+ blasts cells sorted from MLL leukemia patients were either cultured in IMDM medium supplemented with 20% FBS and 10 ng/mL of SCF, TPO, Flt-3 L, IL-3, and IL-6 [29].…”