Mini-reviewAcute myelogenous leukemia stem cells: From Bench to Bedside
Highlights
► Leukemia stem cells are a rare subset of cells capable of self-renewal and initiating leukemia. ► Studies show that high leukemia stem cell burden is associated with poor prognosis. ► Various pre-clinical and clinical trials targeting leukemia stem cells are in development.
Introduction
Despite much advancement in the treatment of acute myelogenous leukemia (AML) over the past three decades, the prognosis remains poor. New cytogenetic markers such as the Flt-3/ITD and NPM1 mutations now aid prognosis, but these discoveries have not translated to significant advancements in survival for the majority of patients with AML. Current chemotherapy regimens employing a backbone of cytarabine combined with an anthracycline have remained largely unchanged since 1973. This treatment regimen is capable of reducing the tumor burden (i.e. the total blast population) and produces a complete remission (CR) in almost 70% of patients. Despite this and the addition of allogeneic stem cell transplant in certain high-risk groups or in those with a matched sibling, most patients will ultimately relapse and approximately 60% of patients will succumb to their disease [1]. Pediatric patients below 15 years of age, while faring better, only have a survival rate approaching 60% [2].
Due to the high incidence of relapse in AML, it is clear that that there is a rare subset of malignant cells that are not effectively eliminated by current treatment regimens [3]. There is a growing opinion that these cells have stem cell-like properties and have been termed leukemia stem cells (LSCs). Independent of the specific cell that gives rise to LSCs, LSCs may share properties with normal hematopoietic stem or progenitor cells (HSCs/HPCs) that make them difficult to target with conventional cancer treatments [4]. Fundamental to their function is their ability to self-renew and give rise to more differentiated progeny. This allows them to maintain a small population of cells capable of recapitulating disease. Like HSCs, LSCs tend to be quiescent, remaining in G0. Furthermore, increasing evidence indicates that LSCs displace normal HSCs from their niche, appropriating its resources to maintain themselves [3], [5], [6]. Targeting LSCs has the promise to eradicate AML and will involve novel therapies that will exploit the differences between these cells and HSCs. This review will discuss strategies used to identify LSCs and developing therapies that selectively target them.
Section snippets
Identifying LSCs and their clinical implications
LSCs were initially characterized in human AML by Bonnet and Dick when they isolated subpopulations of cells from AML patient samples based on their immunophenotype, and xenotransplanted them into NOD/SCID mice. They discovered that the CD34+CD38- expressing subpopulation was exclusively capable of serially transplanting these immunodeficient mice [7]. This finding supported previous evidence of a functional leukemia initiating cell (LIC) defined by its ability to engraft immunocompromised mice
Targeting LSCs
Due to the relative resistance of LSCs to traditional cancer therapies such as chemotherapy, radiation and HSCT, new approaches are currently in development that specifically target the LSC population. LSCs have many attributes that distinguish them from the general blast population and make them more similar to stem cells. In order to eradicate LSCs, it is crucial to overcome the properties that can make them resistant to therapy such as their quiescence, ability to self-renew, and modify the
Disrupting the LSC microenvironment
Cells rely on interactions with other cells in order to function properly and LSCs are no exception. There is evidence from murine xenotransplant models that leukemic cells infiltrate the bone marrow niche, displace HSCs, and use the niche to create an environment hospitable for themselves [24]. Within this niche, LSCs are able to send and receive signals that influence their ability to self-renew, maintain their quiescence, activate pro-growth signals, and inactivate apoptosis pathways. These
Eliminating LSC self-renewal mechanisms
There are a variety of signaling pathways that allow HSCs to self-renew such as Notch, homeobox (HOX), hedgehog, and the Wnt/beta-catenin signaling pathways [40]. While the details of these signaling pathways in both HSCs and leukemia are still not completely known, there are indications that LSCs rely on these pathways for self-renewal. In a recent report by Wang et al. [41], the authors transformed either HSCs or granulocyte–macrophage progenitors (GMP) with either HOXA9 and MEIS1a oncogenes
Targeting LSC growth factors and regulators of apoptosis
Leukemia stem cells appear to be dependent on several survival pathways within the cell leading to aberrant growth and escape from apoptosis. It was previously demonstrated that nuclear factor kappa B activity is elevated in LSCs [43]. NF-κB is a transcription factor active in promoting growth and anti-apoptotic activity within the cell. NF-κB is normally inhibited by the Inhibitor of kappa B alpha (IkBa) family of proteins, which sequester the protein in the cytoplasm not allowing it to enter
Targeting cell surface antigens
Recently, many cell surface antigens have been described showing increased expression in LSCs as compared to HSCs, making these antigens potential therapeutic targets. These antigens include CD123, CD44, CLL-1, CD47, CD25 and CD32 [56]. Various ways of targeting cell surface antigens currently exist and are currently in clinical trials in many illnesses. These include monoclonal antibodies (Ab), immunotoxins, chimeric antigen receptor modified T-cells (CAR T-cells) and nanoparticles containing
Genomic approaches to targeting LSCs
The process of devising new drugs to target LSCs is hindered by the lack of a defined LSC phenotype. While surface markers can be used to identify populations enriched in LSC activity, the LSC potential of any one cell is unknown and the proportion of cells demonstrating LSC activity in functional assays is rather low. Thus, given the tremendous effort required to find a single compound, it is of interest to capture the molecular changes caused by known anti-LSC compounds to accelerate the
Conclusion
For decades, it has been known that there is a subpopulation of AML cells that are resistant to traditional cancer therapies and lead to relapse in the majority of patients with this disease. Over the past two decades, the ability to identify and sort different subpopulations of cells and engraft them into immunocompromised mice has allowed for the ability to define these cells as LSCs. These cells exhibit many qualities found in HSCs such as the ability to both self-renew and to give rise to
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