Current Understanding of the Role of Autophagy in the Treatment of Myeloid Leukemia

Abstract

The most important issues in acute myeloid leukemia are preventing relapse and treating relapse. Although the remission rate has improved to approximately 80%, the 5-year survival rate is only around 30%. The main reasons for this are the high relapse rate and the limited treatment options. In chronic myeloid leukemia patients, when a deep molecular response is achieved for a certain period of time through tyrosine kinase inhibitor treatment, about half of them will reach treatment-free remission, but relapse is still a problem. Therefore, potential therapeutic targets for myeloid leukemias are eagerly awaited. Autophagy suppresses the development of cancer by maintaining cellular homeostasis; however, it also promotes cancer progression by helping cancer cells survive under various metabolic stresses. In addition, autophagy is promoted or suppressed in cancer cells by various genetic mutations. Therefore, the development of therapies that target autophagy is also being actively researched in the field of leukemia. In this review, studies of the role of autophagy in hematopoiesis, leukemogenesis, and myeloid leukemias are presented, and the impact of autophagy regulation on leukemia treatment and the clinical trials of autophagy-related drugs to date is discussed.

Keywords: acute myeloid leukemia; chronic myeloid leukemia; clinical trial; cyclodextrin; folate receptor; folic acid; hydroxypropyl-β-cyclodextrin; mitophagy.

Figure 1

Autophagy pathway. The membrane that forms at the contact site between the mitochondria and endoplasmic reticulum extends to surround the degradation products at both ends and closes (autophagosome). After that, it fuses with the lysosome to become an autolysosome, and the internal contents are broken down by digestive enzymes. Lysosomes are regenerated from the autolysosome.

Figure 2

Formation of autophagosomes. The ULK1 complex, which is involved in the initiation of autophagy, is inhibited by the mTORC1 kinase complex, so autophagy is induced when TORC1 is inactivated by factors such as nutrient starvation. When the ULK1 complex migrates to a subdomain of the endoplasmic reticulum (ER), the PI3K complex I is recruited, and the production of PI3P production increases. The PI3P-binding protein WIPI binds to it and accumulates at the site of autophagosome formation together with its partner ATG2. ATG2 anchors the ER and the phagophore and transports lipids. The ATG12 system is a system in which ATG12 and ATG5 are covalently bound to each other via a ubiquitin-like binding reaction. The ATG12–ATG5 complex forms a ternary complex with ATG16L and localizes to the phagophore, where it determines the location of amide bond formation between ATG8 family proteins (LC3B) and PE. LC3B-PE localizes to the inner and outer membranes of the phagophore and autophagosome, and it functions in membrane elongation and closure. TORC1, target of rapamycin complex 1; ULK1, Unc51-like kinase 1; PI3K, phosphatidylinositol-3 kinase; PI3P, phosphatidylinositol-3-phosphate; WIPI, WD repeat domain phosphoinositide-interacting; ATG, autophagy-related protein; LC3B, light chain 3B; FIP200, focal adhesion kinase interacting protein; VPS34, vacuolar protein sorting 34.

Figure 3

Effects of activating and inhibiting autophagy on leukemia cells. Although various anticancer drugs and radiation therapy have antitumor effects, they also activate autophagy in leukemia cells. This leads to resistance to antileukemia therapy and the progression of leukemia. It is thought that the use of autophagy inhibitors in combination can compensate for this drawback. However, drugs that promote autophagy are thought to promote the activation of autophagy beyond the maintenance of leukemia homeostasis, leading to cell death.