Autophagy and mitochondrial metabolism: insights into their role and therapeutic potential in chronic myeloid leukaemia

Abstract

Despite the development of selective BCR-ABL-targeting tyrosine kinase inhibitors (TKIs) transforming the management of chronic myeloid leukaemia (CML), therapy-resistant leukaemic stem cells (LSCs) persist after TKI treatment and present an obstacle to a CML cure. Recently, we and others have made significant contributions to the field by unravelling survival dependencies in LSCs to work towards the goal of eradicating LSCs in CML patients. In this review, we describe these findings focusing on autophagy and mitochondrial metabolism, which have recently been uncovered as two essential processes for LSCs quiescence and survival respectively. In addition, we discuss the therapeutic potential of autophagy and mitochondrial metabolism inhibition as a strategy to eliminate CML cells in patients where the resistance to TKI is driven by BCR-ABL-independent mechanism(s).

Natural and Semisynthetic Pentacyclic Triterpenes for Chronic Myeloid Leukemia Therapy: Reality, Challenges and Perspectives

“…Regarding CML, CDDO−Me has been shown to effectively inhibit the cell growth of the KBM5 wild‐type and T315I mutated cells, with a great 96‐hour IC 50 of 205 and 221 nM, respectively. Leukemic stem cells, many times responsible for chemoresistance or disease relapse, present higher expression of genes involved in oxidative phosphorylation than normal hematopoietic stem cells, therefore exhibiting increased mitochondrial performance [56] . In agreement with these findings, KBM5‐T315I cells have shown higher baseline oxygen consumption rates than wild‐type KBM5, and treatment with 100 nM CDDO−Me decreased the oxygen use of both cell lines, while increasing ROS production leading to loss of mitochondrial membrane potential.…”

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

“…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 ).…”

Folic Acid-Appended Hydroxypropyl-β-Cyclodextrin Exhibits Potent Antitumor Activity in Chronic Myeloid Leukemia Cells via Autophagic Cell Death

“…Autophagy is involved in drug resistance, survival, and growth in the tumor environment in various solid tumors and hematological malignancies, and the regulation of autophagy has attracted attention as a promising target for cancer therapy [ 24 , 25 , 26 ]. Knockout of Atg3, a gene essential for autophagy, in a CML mouse model markedly delays the onset of CML, indicating that autophagy underlies the pathogenesis of CML [ 27 ].…”