For more than 50 years, investigators have considered a malignant stem cell as the potential origin of and a key therapeutic target for acute myeloid leukemia (AML) and other forms of cancer.1-4 The ...nature and existence of tumor-initiating cells for leukemia and other malignancies have long been the subject of intense and rigorous study; indeed, the promise of the potential to eradicate such cells is clear. However, until recently, deficiencies in our understanding of the nature of these cell populations, coupled with a limited ability to therapeutically exploit their weaknesses, have been limiting factors in realizing the goal of targeting leukemic stem cells (LSCs). Exciting new insights into the fundamental underpinnings of LSCs are now being made in an era in which drug development pipelines offer the potential to specifically target pathways of significance. Therefore, the focus in this new era, characterized by the confluence of understanding LSCs and the ability to target them, is shifting from “if it can be done” to “how it will be done.” Moving from a theoretical stage to this hopeful era of possibilities, new challenges expectedly arise, and our focus now must shift to determining the best strategy by which to target LSCs, with their well-documented heterogeneity and readily evident intra- and interpatient variability. The purpose of this review is therefore both to summarize the key scientific findings pertinent to AML LSC targeting and to consider methods of clinical evaluation that will be most effective for identifying successful LSC-directed therapies.
Malignant stem cells have long been considered a key therapeutic target in leukemia. Therapeutic strategies designed to target the fundamental biology of leukemia stem cells while sparing normal ...hematopoietic cells may provide better outcomes for leukemia patients. One process in leukemia stem cell biology that has intriguing therapeutic potential is energy metabolism. In this article we discuss the metabolic properties of leukemia stem cells and how targeting energy metabolism may provide more effective therapeutic regimens for leukemia patients. In addition, we highlight the similarities and differences in energy metabolism between leukemia stem cells and malignant stem cells from solid tumors.
Cancer stem cells have unique metabolic biology that can in some instances be exploited for therapeutic intervention. This review summarizes the progress and challenges inherent to this field, including metabolic flexibility, inter and intra-patient heterogeneity, and commonalities and differences in energy metabolism between leukemia and solid tumors.
The investigation and study of cancer stem cells (CSCs) have received enormous attention over the past 5 to 10 years but remain topics of considerable controversy. Opinions about the validity of the ...CSC hypothesis, the biological properties of CSCs, and the relevance of CSCs to cancer therapy differ widely. In the following commentary, we discuss the nature of the debate, the parameters by which CSCs can or cannot be defined, and the identification of new potential therapeutic targets elucidated by considering cancer as a problem in stem cell biology.
Acute myelogenous leukemia is propagated by a subpopulation of leukemia stem cells (LSCs). In this article, we review both the intrinsic and extrinsic components that are known to influence the ...survival of human LSCs. The intrinsic factors encompass regulators of cell cycle and prosurvival pathways (such as nuclear factor kappa B NF-κB, AKT), pathways regulating oxidative stress, and specific molecular components promoting self-renewal. The extrinsic components are generated by the bone marrow microenvironment and include chemokine receptors (CXCR4), adhesion molecules (VLA-4 and CD44), and hypoxia-related proteins. New strategies that exploit potentially unique properties of the LSCs and their microenvironment are discussed.
Most forms of chemotherapy employ mechanisms involving induction of oxidative stress, a strategy that can be effective due to the elevated oxidative state commonly observed in cancer cells. However, ...recent studies have shown that relative redox levels in primary tumors can be heterogeneous, suggesting that regimens dependent on differential oxidative state may not be uniformly effective. To investigate this issue in hematological malignancies, we evaluated mechanisms controlling oxidative state in primary specimens derived from acute myelogenous leukemia (AML) patients. Our studies demonstrate three striking findings. First, the majority of functionally defined leukemia stem cells (LSCs) are characterized by relatively low levels of reactive oxygen species (termed “ROS-low”). Second, ROS-low LSCs aberrantly overexpress BCL-2. Third, BCL-2 inhibition reduced oxidative phosphorylation and selectively eradicated quiescent LSCs. Based on these findings, we propose a model wherein the unique physiology of ROS-low LSCs provides an opportunity for selective targeting via disruption of BCL-2-dependent oxidative phosphorylation.
► LSC are prospectively isolated from the bulk tumor on the basis of low ROS levels ► Metabolic dependencies discriminating LSCs, bulk tumor, and normal HSCs are described ► BCL-2 is identified as a regulator of LSC mitochondrial respiration ► BCL-2 pharmacologic inhibitors demonstrate LSC-specific targeting
Human leukemia stem cells upregulate BCL-2 expression as a result of relying on oxidative phosphorylation to produce energy and can therefore be targeted with BCL-2 inhibitors.
While a broad range of expertise has recently come to bear on the intriguing topic of “cancer stem cells,” the overall relevance of stem cells as they relate to cancer remains in dispute. In this ...commentary, underlying points of contention are described with the aim of defining focal points for discussion and future consideration.
In this study we interrogated the metabolome of human acute myeloid leukemia (AML) stem cells to elucidate properties relevant to therapeutic intervention. We demonstrate that amino acid uptake, ...steady-state levels, and catabolism are all elevated in the leukemia stem cell (LSC) population. Furthermore, LSCs isolated from de novo AML patients are uniquely reliant on amino acid metabolism for oxidative phosphorylation and survival. Pharmacological inhibition of amino acid metabolism reduces oxidative phosphorylation and induces cell death. In contrast, LSCs obtained from relapsed AML patients are not reliant on amino acid metabolism due to their ability to compensate through increased fatty acid metabolism. These findings indicate that clinically relevant eradication of LSCs can be achieved with drugs that target LSC metabolic vulnerabilities.
•Leukemia stem cells (LSCs) rely on amino acids for survival•LSCs use amino acids to fuel oxidative phosphorylation (OXPHOS)•Venetoclax with azacitidine inhibits OXPHOS in LSCs from leukemia patients•Venetoclax with azacitidine targets OXPHOS by inhibiting amino acid metabolism
By interrogating metabolic properties of human acute myeloid leukemia, Jones et al. reveal increased amino acid metabolism in leukemia stem cells (LSCs), which rely on amino acids for oxidative phosphorylation and survival. Venetoclax with azacitidine induces LSC toxicity by decreasing amino acid uptake.
Adipose tissue (AT) has previously been identified as an extra-medullary reservoir for normal hematopoietic stem cells (HSCs) and may promote tumor development. Here, we show that a subpopulation of ...leukemic stem cells (LSCs) can utilize gonadal adipose tissue (GAT) as a niche to support their metabolism and evade chemotherapy. In a mouse model of blast crisis chronic myeloid leukemia (CML), adipose-resident LSCs exhibit a pro-inflammatory phenotype and induce lipolysis in GAT. GAT lipolysis fuels fatty acid oxidation in LSCs, especially within a subpopulation expressing the fatty acid transporter CD36. CD36+ LSCs have unique metabolic properties, are strikingly enriched in AT, and are protected from chemotherapy by the GAT microenvironment. CD36 also marks a fraction of human blast crisis CML and acute myeloid leukemia (AML) cells with similar biological properties. These findings suggest striking interplay between leukemic cells and AT to create a unique microenvironment that supports the metabolic demands and survival of a distinct LSC subpopulation.
Display omitted
•Gonadal adipose tissue (GAT) serves as a reservoir for LSCs•Interplay between leukemia cells and GAT fuels leukemia cell fatty acid metabolism•CD36 segregates LSCs into two metabolically and functionally distinct subsets•GAT provides a niche that confers chemo-resistance for CD36+ LSCs
Ye et al. show that LSCs co-opt the adipose tissue niche to create a microenvironment that supports leukemic growth and resistance to chemotherapy. They also detect metabolically and functionally distinct mouse and human LSC subpopulations delineated by expression of the fatty acid transporter CD36.
Receptor-interacting protein kinase-3 （RIP3 or RIPK3） is an essential part of the cellular machinery that executes ＂programmed＂ or ＂regulated＂ necrosis. Here we show that programmed necrosis is ...activated in response to many chemotherapeutic agents and contributes to chemotherapy-induced cell death. However, we show that RIP3 expres- sion is often silenced in cancer cells due to genomic methylation near its transcriptional start site, thus RIP3-depen- dent activation of MLKL and downstream programmed necrosis during chemotherapeutic death is largely repressed. Nevertheless, treatment with hypomethylating agents restores RIP3 expression, and thereby promotes sensitivity to chemotherapeutics in a RIP3-dependent manner. RIP3 expression is reduced in tumors compared to normal tissue in 85% of breast cancer patients, suggesting that RIP3 deficiency is positively selected during tumor growth/develop- ment. Since hypomethylating agents are reasonably well-tolerated in patients, we propose that RIP3-deficient cancer patients may benefit from receiving hypomethylating agents to induce RIP3 expression prior to treatment with con- ventional chemotherapeutics.
PDF
