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November-December 2019, Volume 16, Issue 6
Outfoxing OXPHOS: Amino Acid Metabolism and the Leukemia Stem Cell
Kristen M. O'Dwyer, MD Assistant Professor of Medicine
Wilmot Cancer Institute, University of Rochester, Rochester, NY
Jane L. Liesveld, MD Professor of Medicine, Hematology/Oncology Division
Wilmot Cancer Institute, University of Rochester School of Medicine, Rochester, NY
Jones CL, Stevens BM, D'Alessandro A, et al. Cysteine depletion targets leukemia stem cells through inhibition of electron transport complex II. Blood. 2019;134:389-394.
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.
Collectively, the results support the likelihood that cysteine metabolism is an essential metabolic process for the LSCs in AML. It remains to be determined if depletion of individual amino acids would be enough to selectively eradicate LSCs. Focusing on the fundamental physiologic characteristics of the LSC, properties that are conserved from patient to patient despite the chromosomal or genetic heterogeneity, may provide a rational treatment approach for those patients with no other "targetable" mutation. Additionally, this study provides further insight into the mechanism of venetoclax resistance.
While a phase III trial testing azacitidine versus azacitidine and venetoclax in older patients has been conducted (NCT02993523), final results are awaited. It will be of interest to see if the combination arm resulted in durable complete remissions as might be expected if LSCs are indeed suppressed by venetoclax plus a hypomethylating agent. Furthermore, this combination has not been tested yet in younger patients, nor has venetoclax been tested in combination with other cytotoxic chemotherapies or in maintenance settings where ongoing LSC suppression would be critical. Focusing on the unique metabolic requirements of LSCs may provide insight into how best to eradicate this OXPHOS-dependent cell as the source of relapse.
Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730-737.
Lapidot T, Sirard C, Vormoor J, et al. A cell initiative human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645-648.
Jordan CT. Unique molecular and cellular features of acute myelogenous leukemia stem cells. Leukemia. 2002;16:559-562.
Rosen JM, Jordan CT. The increasing complexity of the cancer stem cell paradigm. Science. 2009;324:1670-1673.
Ho TC, LaMere M, Stevens BM, et al. Evolution of acute myelogenous leukemia stem cell properties after treatment and progression. Blood. 2016;128:1671-1678.
Pei S, Minhajuddin M, Callahan KP, et al. Targeting aberrant glutathione metabolism to eradicate human acute myelogenous leukemia cells. J Biol Chem. 2013;288:33542-33558.
Legadinou ED, Sach A, Callahan K, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013;12:329-341.
Jones CL, Stevens BM, D'Alessandro A, et al. Inhibition of amino acid metabolism selectively targets human leukemia stem cells. Cancer Cell. 2018;34:724-740.e4.
Dr. O'Dwyer and Dr. Liesveld indicated no relevant conflicts of interest. back to top
Ask the Hematologist Compendium
A new Compendium providing updated clinical information to "Ask the Hematologist" articles published in The Hematologist from 2010 to 2015 is now available.