Lysosomes in Stem Cell Quiescence: A Potential Therapeutic Target in Acute Myeloid Leukemia

Abstract

Lysosomes are cellular organelles that regulate essential biological processes such as cellular homeostasis, development, and aging. They are primarily connected to the degradation/recycling of cellular macromolecules and participate in cellular trafficking, nutritional signaling, energy metabolism, and immune regulation. Therefore, lysosomes connect cellular metabolism and signaling pathways. Lysosome's involvement in the critical biological processes has rekindled clinical interest towards this organelle for treating various diseases, including cancer. Recent research advancements have demonstrated that lysosomes also regulate the maintenance and hemostasis of hematopoietic stem cells (HSCs), which play a critical role in the progression of acute myeloid leukemia (AML) and other types of cancer. Lysosomes regulate both HSCs' metabolic networks and identity transition. AML is a lethal type of blood cancer with a poor prognosis that is particularly associated with aging. Although the genetic landscape of AML has been extensively described, only a few targeted therapies have been produced, warranting the need for further research. This review summarizes the functions and importance of targeting lysosomes in AML, while highlighting the significance of lysosomes in HSCs maintenance.

Keywords: AML; HSCs; NSCs; apoptosis; lysosomes; mitochondria.

Figure 1

The lysosome surface is a hub of signaling activity. Several proteins found in lysosomal membranes are involved in various signaling cascades. The vacuolar-type H⁺ ATPase (V-ATPase) is a proton pump that regulates pH. mTORC1 connects metabolism and signaling. Intra- and extra-luminal amino acid signaling may affect the mTORC1 signaling pathway’s components. The amino acid transporter SLC38A9 detects arginine in the lysosomal lumen and activates mTORC1 via the Rag GTPases and Ragulator complex. A leucine sensor in the cytosol, Sestrin 2, controls mTORC1 activity with the assistance of GATOR proteins. mTORC1 also affects lysosome biogenesis adversely. Ca²⁺ triggers the initiation of lysosome biogenesis. Once Ca²⁺ is released into the cytoplasm, it dephosphorylates TFEB, allowing it to translocate to the nucleus, where it aids in the transcription of the CLEAR network genes and activates lysosomal and autophagic transcription. Transmembrane proteins such as LAMPs are involved in autophagy, lipid transport, and immunological response. SYT7 is a calcium-dependent membrane protein involved in lysosomal exocytosis.

Figure 2

Impairment of the lysosome induces apoptosis. Apoptosis is triggered by lysosomal damage in a mitochondrial-dependent manner. BID is cleaved into tBid by damaged lysosomes, which increases BAX oligomorphism via inducing Bcl-2 degradation by cathepsins. As a result, BAX is translocated to the mitochondrial outer membrane (MOM), where it interacts with mitochondrial permeability y transition pore (MPTP) to release cytochrome C (Cyto C) and triggers apoptosis. Necroptosis occurs when lysosomal activity is inhibited, resulting in the accumulation of necrosome components (such as RIPK1 and RIPK3) and the release of hydrolyzed caspase 8. The necroptosis executor (MLKL) is phosphorylated and translocated to the cell membrane or organelle membrane, resulting in necrosis. Pyroptosis is induced by damaged lysosomes through cleavage of GSDMD into GSDMD-N by releasing CTSG, activation of NLRP3, and caspase-1 by the release of CTSB. Pyroptosis is induced by damaged lysosomes through the cleavage of GSDMD into GSDMD-N by the release of cathepsin G and the activation following that. Pyroptosis results in cell perforation and release of large amounts of interleukin-1 and interleukin-18.

Figure 3

Autophagy and lysosomal pathway. Cytoplasmic cargo is delivered to lysosomes through autophagy. Macroautophagy includes compartmentalizing cytoplasmic payloads in LC3-coated double-membrane vesicles, known as autophagosomes. Structures known as autolysosomes are formed when autophagosomes fuse with lysosomes, and lysosomal hydrolases break down the damaged organelle. The autophagic lysosome reformation process recycles lysosomal components from autolysosomes once cargo breakdown is complete. The recognition of cytoplasmic substrates containing an accessible KFERQ-like motif by HSC70 is vital for chaperone-mediated autophagy. The HSC70-substrate complex is recognized at the lysosomal membrane by LAMP2A. LAMP2A oligomerization then forms a translocation channel, transporting the substrate into the lysosomal lumen. The LAMP2A channel disassembles into monomers after substrate delivery, allowing substrate delivery. Microautophagy entails the transport of cargo into the lysosomal lumen via interaction. Direct interaction into the endosomal lumen during endosomal microautophagy transport cargo to late endosomes, where it forms multivesicular bodies. The lysosomes then join the multivesicular bodies to degrade the cargo. Endosomal microautophagy delivers cargo via ESCRT-machinery.

Figure 4

Lysosomes are abundant in quiescent HSCs. (A) Schematic representation shows quiescent HSCs are abundant in lysosomes. (B) Schematic representation shows quiescent HSCs are abundant in lysosomes and have poor mitochondrial lysosomal clearance. HSCs are primed by acidification and activation of lysosomes, possibly through mTORC1 activation. Lysosomes keep HSCs dormant by sequestering and storing old and defective organelles and proteins; lysosomal breakdown and release of metabolites coincide with and contribute to HSC activation and priming. (C) Lysosomes are critical for the maintenance of HSCs due to their asymmetric inheritance, which affects cell fate during cell division.

Figure 5

Different strategies for modulation of lysosomes and their functions. Lysosomes are known to link with many signaling pathways, allowing for multiple targeting options. Since autophagic pathways play different roles in cancer, various methods exist to inhibit/suppress or activate lysosomes. Inhibiting mTORC1 may indirectly enhance autophagy. Lysosomotropic chemicals have the potential to disrupt the membrane and thus prevent lysosome fusion. Inhibitors of V-ATPase have an impact on several pH-sensitive lysosomal enzymes. HSP70 inhibitors may be used to enhance the impact of lysosomotropic drugs that protect against HSP70. Lysosomal exocytosis releases cathepsins into the extracellular environment, promoting extracellular matrix breakdown and malignant cell invasion. Cathepsin protease inhibitors have the potential to be utilized as a treatment option.

Figure 6

Large lysosomes contribute to resistance to chemotherapy in cancer. (A) In cancer cells (AML), enlarged lysosomes may make them more resistant to chemotherapy by concealing therapeutic chemicals inside lysosomes. (B) Lysosome-targeting therapies in cancer (AML): The lysosome membranes are damaged, enabling enzymes to release into the cytosol. Disruption of lysosomal function due to hyper- or hypo-acidification increases medication resistance. Inhibiting pump (v-ATPase) or channel activity may induce lysosome-dependent cell death.