Hematopoietic Stem Cells: Normal Versus Malignant

Abstract

Significance: The long-term hematopoietic stem cell (LT-HSC) demonstrates characteristics of self-renewal and the ability to manage expansion of the hematopoietic compartment while maintaining the capacity for differentiation into hematopoietic stem/progenitor cell (HSPC) and terminal subpopulations. Deregulation of the HSPC redox environment results in loss of signaling that normally controls HSPC fate, leading to a loss of HSPC function and exhaustion. The characteristics of HSPC exhaustion via redox stress closely mirror phenotypic traits of hematopoietic malignancies and the leukemic stem cell (LSC). These facets elucidate the HSC/LSC redox environment as a druggable target and a growing area of cancer research. Recent Advances: Although myelosuppression and exhaustion of the hematopoietic niche are detrimental side effects of classical chemotherapies, new agents that modify the HSPC/LSC redox environment have demonstrated the potential for protection of normal HSPC function while inducing cytotoxicity within malignant populations.

Critical issues: New therapies must preserve, or only slightly disturb normal HSPC redox balance and function, while simultaneously altering the malignant cellular redox state. The cascade nature of redox damage makes this a critical and delicate line for the development of a redox-based therapeutic index.

Future directions: Recent evidence demonstrates the potential for redox-based therapies to impact metabolic and epigenetic factors that could contribute to initial LSC transformation. This is balanced by the development of therapies that protect HSPC function. This pushes toward therapies that may alter the HSC/LSC redox state but lead to initiation cell fate signaling lost in malignant transformation while protecting normal HSPC function. Antioxid. Redox Signal.

Keywords: HSC; LSC; hematopoiesis; redox-active compound; stem cell function.

FIG. 1.

The bone marrow compartment contains a complex and highly regulated hierarchy of cell types tasked with maintaining the production and balance of all cells in the blood system. Beginning with the most primitive CD34⁺ LT-HSCs, the ability to self-renew and differentiate to downstream phenotypes defines the LT-HSC pool with a decreased capacity for self-renewal as differentiation occurs. From the MPP pool, both lymphoid and myeloid cell types develop and eventually differentiate into terminal effector cell types seen in the periphery. CD34, cluster of differentiation protein 34; CLP, common lymphoid progenitor; CMP, common myeloid leukemia; LT-HSC, long-term hematopoietic stem cell; MPP, multipotent progenitor cell; ST-HSC, short-term hematopoietic. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

The bone marrow compartment demonstrates oxygen concentrations that range from 1% (furthest for the blood supply) to 7% (closest to the blood supply). Low oxygen concentrations have been referenced as a factor contributing to the protection and quiescence of HSCs. However, upon transformation, LSCs may demonstrate increased levels of metabolism and ROS levels, while maintaining a lower antioxidant capacity than their downstream progeny. This difference, a product of the oxygen environment, may allow for a differential redox insult and targeting of LSCs over normal HSCs driven by the introduction of a redox-active compound. HSC, hematopoietic stem cell; HSPC, hematopoietic stem/progenitor cell; LSC, leukemic stem cell; ROS, reactive oxygen species. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

Normal and malignant HSCs demonstrate differences in the regulation and management of the antioxidant system. Normal HSCs express higher levels of primary antioxidant enzymes SOD and CAT. Malignant HSCs are subject to elevated levels of ROS produced by NOX enzyme and rely on higher cellular concentrations of GSH as well as the GSH metabolic system to manage the malignant HSC redox state. CAT, catalase; GPx, glutathione peroxidase; GR, glutathione reductase; GSH, reduced glutathione; GSSG, oxidized glutathione; H₂O₂, hydrogen peroxide; NADPH, nicotinamide adenine dinucleotide phosphate; NOX, nicotinamide adenine dinucleotide phosphate oxidase; SOD, superoxide dismutase. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

A schematic diagram demonstrates the differential effect and graded response of HSCs to various redox-active compounds and ROS inducers. Normal hematopoiesis is characterized by primitive LT-HSCs that have the ability to self-renew and differentiate into any other cell type. As differentiation occurs, progenitor cell types lose their ability to self-renew. This process is accelerated in the presence of potent ROS induces, such as conventional chemotherapeutic agents and ionizing radiation. Response to these stimuli results in DNA damage response and activation of signaling that results in the upregulation of cellular senescence and apoptosis. New evidence now suggests that mild ROS inducers have an opposite effect wherein generation of a mild ROS milieu results in the activation of antioxidant defense pathways leading to an improvement in HSC function. The result is a graded response to different levels of ROS stimulant that leads to variations of HSC function and either exhaustion or strengthening of the hematopoietic niche. Atm, ataxia-telangiectsia mutated; BSO, buthionin sulfoximine; DOX, doxorubicin; MnP, Mn porphyrin; Nq01, NAD(P)H dehydrogenase quinone 1; Nrf2, nuclear factor (erythroid-derived 2)-like 2. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 5.

The prosurvival response of normal HSCs to mild pro-oxidants has led to the concept of differential response to redox cycling compounds between normal and malignant HSCs. Redox-active compounds will use the normal levels of ROS produced by healthy HSCs to activate an antioxidant response leading to increased proliferation and HSC function. Conversely, LSCs perpetually produce elevated levels of superoxide via aberrant constitutive enzyme activity that can be used by redox-active compounds to produce second messenger ROS such as hydrogen peroxide. This may lead to LSC senescence and death. The theoretical result is the protection of normal HSC function with simultaneous cytotoxic, anticancer affects in the LSC population. AP-1, activating protein-1. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 6.

The table summarizes the redox-active compounds that have been discussed throughout this review as well as their effects within their indicated disease states and normal HSPC populations where applicable. This dual application highlights the potential for selective targeting of malignant populations while offering protection to normal HSPCs for many redox-active compounds discussed and cited within this review. ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; FLT3-ITD, FMS-like tyrosine kinase 3-internal tandem repeat; GCLC, glutamate-cysteine ligase catalytic subunit; GCLM, glutamate-cysteine ligase regulatory subunit; LSD1, lysine specific histone demethylase 1A; MDS, myelodysplastic syndrome; MM, multiple myeloma; NF-κB, nuclear factor-κB; PARP, poly (ADP-ribose) polymerase; PBMC, peripheral blood mononuclear cell; TRAIL, TNF-related apoptosis-inducing ligand; TXNIP, thioredoxin-interacting protein.