![Figure 1. Effect of autophagy modulation on leukemia development. (A) Core machinery and signaling involved in macroautophagy. The ULK1, mATG13, FIP200, and ATG101 complex controls the initiation step of de novo isolation of a portion of intracellular membrane referred to as a phagophore. Then, 2 complexes composed of either BECLIN-1-Atg14/ATG14L-VPS34-VPS15 or BECLIN-1-UVRAG-BIF-1-VPS34-VPS15 control the nucleation of this phagophore. Finally, 2 ATG7-processed conjugation systems, ATG12-ATG5 and LC3-II, play a significant role in the elongation and closure of the phagophore to generate a structure termed autophagosome. This autophagosome undergoes 2 maturation steps: first, it fuses with endosomes to generate an amphisome, which becomes acidified due to the presence of membrane proton pumps provided by endosomes; second, the amphisome fuses with lysosomes to generate autolysosomes capable of enzymatic degradation of the original intravesicular contents. (B) Fluctuations in autophagy activation facilitate leukemia development and promote resistance to front-line therapies. Functional autophagy is required for proper differentiation of HSCs into multiple lineages. Impairment of autophagy promotes accumulation of mitochondrial reactive oxygen species and DNA damage and presumably activates downstream signaling pathways, such as Notch pathway, to block normal HSCs differentiation and switch normal HSCs to preleukemic HSCs (pre–leukemic stem cells [LSCs]). This unstable preleukemic state becomes favorable to overt leukemic transformation by cooperative genetic alterations, such as BCR-ABL or PML-RARA translocations, of HSCs to LSCs. In this context, reduced autophagy stabilizes these oncoproteins. Afterward, some front-line therapies used in various hematopoietic diseases may reactivate a cytoprotective autophagy that counteracts their cytotoxic effects. Therefore, autophagy inhibitors, such as 3-methyladenine (3-MA), Hydroxychloroquine (HCQ), and Bafilomycin A1 (Baf A1), synergize with these therapies to enhance their antileukemic properties and promote cell death.](https://ash.silverchair-cdn.com/ash/content_public/journal/blood/129/5/10.1182_blood-2016-07-692707/4/blood692707f1.jpeg?Expires=1724263808&Signature=cYbWcOh6FCurgwrkp8eMUdBSlXvgFxx9Luse-2mvMWNzmewWUP-5C8uEOste3VJlfZRGPK58LtSnWoMFO4iuIBX8aCa2VxToifHtprFTszyItkPUSU-muaZGHUOcpmnPddm92tHRh6H0-ZSjrykFaHQVwCd9YkqxZ2qUI58HFdUurnPDJ7MjB8moufADF0lvwmvJWkzMG3obYyQLoZWxbMhPLwI2JsUEmEHPTBQZEop-8wTsucxATI1Y5bPnvA2U9P~3WLj6mXAKPpjDK5Mw7yr0srTWBOQXVddzLNPy4rCKfks7CSF~dPEh-4IKQCluO8j5jW0IzMGyZ7IqwJK4HQ__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
Effect of autophagy modulation on leukemia development. (A) Core machinery and signaling involved in macroautophagy. The ULK1, mATG13, FIP200, and ATG101 complex controls the initiation step of de novo isolation of a portion of intracellular membrane referred to as a phagophore. Then, 2 complexes composed of either BECLIN-1-Atg14/ATG14L-VPS34-VPS15 or BECLIN-1-UVRAG-BIF-1-VPS34-VPS15 control the nucleation of this phagophore. Finally, 2 ATG7-processed conjugation systems, ATG12-ATG5 and LC3-II, play a significant role in the elongation and closure of the phagophore to generate a structure termed autophagosome. This autophagosome undergoes 2 maturation steps: first, it fuses with endosomes to generate an amphisome, which becomes acidified due to the presence of membrane proton pumps provided by endosomes; second, the amphisome fuses with lysosomes to generate autolysosomes capable of enzymatic degradation of the original intravesicular contents. (B) Fluctuations in autophagy activation facilitate leukemia development and promote resistance to front-line therapies. Functional autophagy is required for proper differentiation of HSCs into multiple lineages. Impairment of autophagy promotes accumulation of mitochondrial reactive oxygen species and DNA damage and presumably activates downstream signaling pathways, such as Notch pathway, to block normal HSCs differentiation and switch normal HSCs to preleukemic HSCs (pre–leukemic stem cells [LSCs]). This unstable preleukemic state becomes favorable to overt leukemic transformation by cooperative genetic alterations, such as BCR-ABL or PML-RARA translocations, of HSCs to LSCs. In this context, reduced autophagy stabilizes these oncoproteins. Afterward, some front-line therapies used in various hematopoietic diseases may reactivate a cytoprotective autophagy that counteracts their cytotoxic effects. Therefore, autophagy inhibitors, such as 3-methyladenine (3-MA), Hydroxychloroquine (HCQ), and Bafilomycin A1 (Baf A1), synergize with these therapies to enhance their antileukemic properties and promote cell death.
