Outfoxing OXPHOS: Amino Acid Metabolism and the Leukemia Stem Cell

The cancer stem cell paradigm offers one probable explanation for the chemotherapy failures observed in acute myeloid leukemia (AML). The leukemia stem cell (LSC) is a relatively rare and quiescent cell capable of self-renewal and able to generate the leukemia progenitor and the leukemic blast cells in a hierarchical organization that is analogous to normal hematopoiesis.^1-4  As the leukemia progresses, however, the LSC becomes unstable, especially in the relapse setting following cytotoxic chemotherapy.⁵  The clinical consequence of the LSC quiescence and physiology is that chemotherapies currently used for the treatment of AML effectively kill the leukemic blast cells, but they do not eliminate the LSC, therefore creating a reservoir for relapse of the disease and ultimately failure of cytotoxic chemotherapies. In fact, it has been demonstrated in several laboratories that the LSC is refractory to anthracycline and cytarabine treatment,^1,2,4  the core chemotherapies of AML treatment.

To this end, the laboratory of Dr. Craig Jordan and colleagues have been characterizing the LSC in the context of fundamental biology in AML. Their question: does the LSC display unique physiological properties that point to more rational drug treatments for patients with AML? In fact, several paths of analysis suggest the LSC establishes a distinct metabolic environment, as compared to normal HSCs, that is dependent on the control of oxidative state and management of cellular stress.⁶  The Jordan laboratory has demonstrated that oxidative phosphorylation (OXPHOS) is critical for LSC maintenance and survival,⁷  and specifically that the majority of functionally defined LSCs are characterized by relatively low levels of reactive oxygen species (termed “ROS-low”) and aberrant expression of the mitochondrial protein, B-cell lymphoma 2 (BCL-2). Further, the lab expanded the work on the unique metabolic dependencies of the LSC and demonstrated that the LSCs are distinctively reliant on amino acid metabolism to maintain OXPHOS for their survival.⁸   

In the current article, Dr. Courtney Jones and colleagues examine the role of individual amino acids on LSC survival in primary human AML specimens.⁹  By testing the viability of primary AML cells in culture in which single amino acids were depleted, three amino acids (cysteine, arginine, and glutamine) demonstrated a role in sustaining the bulk blast population, but only depletion of cysteine induced death in LSC and progenitor populations. To explore the role of cysteine in LSC biology, the authors examined the metabolism of exogenous isotopically labeled cysteine in the LSC population and found that cysteine is exclusively metabolized into the cellular antioxidant, glutathione (GSH). Further, depletion of cysteine strongly reduced intracellular GSH levels in ROS-low LSCs. Since GSH is essential for maintaining the viability of the ROS-low LSC cells, targeting GSH metabolism, possibly via cysteine depletion, could represent a powerful strategy to induce toxicity toward the LSC population.

The authors further showed that cysteine depletion disrupts other GSH-dependent processes. Specifically, they examined the effect of cysteine depletion on the glutathionylation of succinate dehydrogenase A (SDHA), a subunit of the electron transport chain complex II (ETC II). The current report shows that cysteine depletion leads to decreased SDHA glutathionylation and ETC II activity, resulting in reduced OXPHOS and death of ROS-low LSCs. Building on these findings, the investigators examined cysteine levels in ROS-low LSC specimens from patients with de novo AML who responded to azacitidine and venetoclax and from patients with relapsed/refractory AML who were resistant to azacitadine and venetoclax. They uncovered that cysteine and GSH was depleted in patients who responded to the combination therapy, but not in those who were relapsed/refractory, suggesting that cysteine levels may be a potential biomarker of venetoclax response and that therapies designed to degrade cysteine may be useful in refractory AML.