fig1

Figure 1. Mechanisms of lysosomal-mediated chemoresistance in acute myeloid leukemia (AML) at a glance. Most chemotherapeutic agents get readily sequestered in lysosomes upon entry in AML cells, causing a remarkable expansion of the lysosomal compartment. Lysosomal expansion is accompanied by an increase in pH, inducing exocytosis and, consequently, clearance of chemotherapy from cells. Both mechanisms prevent chemotherapeutic agents from directly interacting with their molecular targets, commonly located in the nucleus. To revert the undesirable sequestration, two main strategies have been proposed, namely, increasing lysosomal pH by inhibiting V-ATPase or pharmacologically inducing lysosomal membrane leakiness, thus releasing chemotherapeutics and additionally eliciting lysosomal-dependent cell death. Conversely, mTORC1 inhibition contributes to lysosomal biogenesis and sequestration capacity, a mechanism that has been traditionally overlooked in translation of mTORC1 inhibitors and that could partly explain their clinical failure. ABCA3: ATP binding cassette subfamily A member 3; CaN: calcineurin; LMP: lysosomal membrane permeabilization; MCOLN1: mucolipin TRP cation channel 1; mTORC1: mammalian target of rapamycin complex 1; TFEB: transcription factor EB; V-ATPase: vacuolar ATPase.