Autophagy in Hematological Malignancies

Abstract

Autophagy is a highly conserved metabolic pathway via which unwanted intracellular materials, such as unfolded proteins or damaged organelles, are digested. It is activated in response to conditions of oxidative stress or starvation, and is essential for the maintenance of cellular homeostasis and other vital functions, such as differentiation, cell death, and the cell cycle. Therefore, autophagy plays an important role in the initiation and progression of tumors, including hematological malignancies, where damaged autophagy during hematopoiesis can cause malignant transformation and increase cell proliferation. Over the last decade, the importance of autophagy in response to standard pharmacological treatment of hematological tumors has been observed, revealing completely opposite roles depending on the tumor type and stage. Thus, autophagy can promote tumor survival by attenuating the cellular damage caused by drugs and/or stabilizing oncogenic proteins, but can also have an antitumoral effect due to autophagic cell death. Therefore, autophagy-based strategies must depend on the context to create specific and safe combination therapies that could contribute to improved clinical outcomes. In this review, we describe the process of autophagy and its role on hematopoiesis, and we highlight recent research investigating its role as a potential therapeutic target in hematological malignancies. The findings suggest that genetic variants within autophagy-related genes modulate the risk of developing hemopathies, as well as patient survival.

Calcium influx, oxidative stress, and apoptosis induced by TRPV1 in chronic myeloid leukemia cells: Synergistic effects with imatinib

“…Autophagy, activated in response to several conditions including oxidative stress and mitochondrial alteration, is an essential pathway aimed at eliminating unwanted intracellular elements, such as unfolded oxidized proteins or damaged organelles, to promote cell survival ( García Ruiz et al, 2022 ). To assess the induction of autophagy by OLDA treatment, we first analyzed the ATG12–ATG5 complex essential for autophagosome formation ( Kharaziha and Panaretakis, 2017 ).…”

“…The autophagy machinery is activated during cellular stresses to digest damaged organelles, unwanted proteins, and intracellular materials. Thus, given that it is indispensable to maintain cellular homeostasis, several reports highlight its anti-tumoral action in CML by controlling ROS and DNA damage ( Baquero et al, 2019 ; García Ruiz et al, 2022 ). It has been demonstrated that CD34 + leukemia stem cells display a high level of autophagic flux, and, more importantly, TKI treatment, as the flip side, stimulates autophagy responsible for leukemia stem cell survival and establishment of drug resistance ( Bellodi et al, 2009 ).…”

Possible mechanism of metabolic and drug resistance with L-asparaginase therapy in childhood leukaemia

“…Amino acid deprivation has been shown to induce the activation of autophagy, which is considered a self-protective mechanism in tumour cells ( 55 – 57 ). Hermanova et al.…”

Autoimmunity and Carcinogenesis: Their Relationship under the Umbrella of Autophagy

“…Autophagy plays an important role in several CSC functions, including maintenance and survival [ 68 , 69 , 70 , 71 , 72 , 73 ], adaptation to the TME [ 74 , 75 , 76 ], migration and invasion [ 77 , 78 ], chemo- and immune-resistance [ 79 , 80 , 81 , 82 ], and metabolic reprogramming [ 83 , 84 , 85 ]. Numerous studies suggest that the inflammatory response in the TME is regulated by autophagy via TAMs and CAFs.…”