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Review
, 18 (11), 1349-83

Redox Control of Leukemia: From Molecular Mechanisms to Therapeutic Opportunities

Affiliations
Review

Redox Control of Leukemia: From Molecular Mechanisms to Therapeutic Opportunities

Mary E Irwin et al. Antioxid Redox Signal.

Abstract

Reactive oxygen species (ROS) play both positive and negative roles in the proliferation and survival of a cell. This dual nature has been exploited by leukemia cells to promote growth, survival, and genomic instability-some of the hallmarks of the cancer phenotype. In addition to altered ROS levels, many antioxidants are dysregulated in leukemia cells. Together, the production of ROS and the expression and activity of antioxidant enzymes make up the primary redox control of leukemia cells. By manipulating this system, leukemia cells gain proliferative and survival advantages, even in the face of therapeutic insults. Standard treatment options have improved leukemia patient survival rates in recent years, although relapse and the development of resistance are persistent challenges. Therapies targeting the redox environment show promise for these cases. This review highlights the molecular mechanisms that control the redox milieu of leukemia cells. In particular, ROS production by the mitochondrial electron transport chain, NADPH oxidase, xanthine oxidoreductase, and cytochrome P450 will be addressed. Expression and activation of antioxidant enzymes such as superoxide dismutase, catalase, heme oxygenase, glutathione, thioredoxin, and peroxiredoxin are perturbed in leukemia cells, and the functional consequences of these molecular alterations will be described. Lastly, we delve into how these pathways can be potentially exploited therapeutically to improve treatment regimens and promote better outcomes for leukemia patients.

Figures

FIG. 1.
FIG. 1.
ROS are elevated in leukemic cells compared with normal cells, leading to differing biological outcomes. (A) The balance of ROS levels is tipped to denote that leukemic cells have higher basal levels of ROS than normal cells (B) Within normal cells (top panel), low levels of ROS are constitutively produced (light shading in the triangle), which contributes to cell proliferation, survival, and motility. As these levels increase (darker shading), oxidative damage can occur to cells that ultimately results in cell death. Leukemic cells (bottom panel) have constitutively elevated levels of ROS (darker shading in the triangle) due to alterations in redox control. However, due to this altered redox status, elevated ROS is beneficial rather than detrimental to leukemic cells. Elevated ROS in leukemic cells not only provides the same benefits as low levels of ROS in normal cells but also promotes genomic instability and drug resistance due to oxidative damage. Ultimately, further elevations in ROS, such as those produced by therapeutic agents, can lead to the death of leukemia cells. ROS, reactive oxygen species.
FIG. 2.
FIG. 2.
Leukemogenesis involves driver and passenger mutations and alterations in ROS. (A) Normal hematopoiesis involves the hematopoietic stem cells (HSCs), a self-replicating progenitor that differentiates into two lineages, common lymphoid progenitors (CLPs) and common myeloid progenitors (CMPs). From these two lineages comes the characterization of lymphocytic and myeloid leukemia. CLPs can further differentiate in lymphoblasts and then B, T, and NK cells. CMPs differentiate into myeloblasts, platelets, and red blood cells. Myeloblasts can then further differentiate into granulocytes. Driver mutations (shaded bolts) occur early in hematopoietic development (HSCs or common progenitors) leading to proliferation and survival. Passenger mutations (white bolts) can occur virtually anywhere along the line of differentiation. (B) HSCs reside within the fairly hypoxic (white) bone marrow niche. Within this niche, HSCs maintain a tight control of low levels of ROS production (light gray star). Upon movement of the HSCs into the oxygen-rich blood stream (gray), ROS levels rise within HSCs (dark gray star), causing them to lose their self-renewing capacity and differentiate into common progenitor (CP) cells.
FIG. 3.
FIG. 3.
Highlighted endogenous routes of leukemic induction of ROS. A myriad of pathways can result in elevated ROS production in leukemic cells. Mutations in the mitochondrial DNA (mtDNA) can lead to alterations of the ETC, resulting in ROS production. Activation of the BCR/ABL, and Flt3-ITD pathways and mutation of Jak can lead to alterations in the NADPH oxidase (NOX) system and ultimately increase ROS levels. In AML, xanthine oxidoreductase activity (XO/XDO) is elevated, which can induce upregulation of ROS. Activating polymorphisms of cytochrome P450, which results in elevated ROS levels, can be found in ALL, AML, and CML. ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; BCR/ABL, breakpoint cluster region–Abelson leukemia virus; CML, chronic myeloid leukemia; ETC, electron transport chain; Flt3, fms-like receptor tyrosine kinase 3; ITD, internal tandem duplication; XO, xanthine oxidase; XDO, xanthine dehydrogenase.
FIG. 4.
FIG. 4.
Mitochondrial ETC is a primary source of ROS in leukemia cells. (A) Electrons from NADH are collected by complex I and shuttled through complexes II and III to cytochrome C (Cyt C). Electrons are further transported to complex IV, or cytochrome C oxidase (COX), where oxygen is converted to water. Electrons then travel through the ATP synthase to create ATP for cell growth and survival. mtDNA encodes 13 of the 87 subunits required for mitochondrial electron transport (the subunits are indicated by gray shading): seven subunits of complex I, one subunit of complex III (cytochrome b), three subunits of complex IV (COXs I, II, and III), and two subunits of the ATP synthase (ATPase 6 and 8). Complexes I and III are the primary sources of ROS production in leukemia (gray stars). (B) Mutations in mtDNA-encoded ETC components found in leukemia. ATP, adenosine triphosphate; ND, NADH dehydrogenase.
FIG. 5.
FIG. 5.
Leukemic oncogenes control NOX assembly and activity in leukemia cells. (A) Leukemic oncogenes, including BCR/ABL, Flt3-ITD, and c-Kit, increase ROS levels, leading to translocation of Nrf2 to the nucleus, where it elevates mRNA expression of p67phox, p47phox, and p40phox. These NOX components then can interact to form the active NOX complex. (B) Leukemic oncogenes also induce elevated levels of NADPH, a rate-limiting substrate for NOX activity, resulting in elevated production of ROS. Nrf2, nuclear factor erythroid 2-related factor 2; P, phosphorylation.
FIG. 6.
FIG. 6.
Transcriptional regulation by Nrf2. (A) Introduction of ROS to a leukemic cell results in oxidation of Keap1, which then releases Nrf2 into the cytosol. Nrf2 translocates to the nucleus, where it interacts with Maf proteins to competitively bind to AREs in the upstream enhancer region of antioxidant genes, increasing their transcription. Upregulation of antioxidants by Nrf2 has been implicated in the proliferation, apoptosis escape, and drug resistance of leukemia cells. (B) ROS displaces Bach1, a transcriptional repressor that competitively binds to AREs, from the enhancer region in leukemia cells. It is then shuttled to the cytosol, where it can be proteolytically degraded, allowing Nrf2 to induce transcription. Such displacement has been correlated with resistance to bortezomib in leukemia. (C) Bach2 normally competitively inhibits Nrf2 transcription. However, BCR/ABL can cause the phosphorylation of Bach2, which results in its retention in the cytoplasm, where it can be degraded. This phenomenon has been correlated with increased antiapoptotic signaling in CML. ARE, antioxidant-response element; Bach2, BTB and CNC homology 2; Keap1, Kelch-like ECH-associated protein 1; HO-1, heme oxygenase 1; Trx, thioredoxin; GST, glutathione-S-transferase; OX, oxidation; P, phosphorylation; TrxR1, Trx reductase 1; Grx, glutaredoxin; Ub, ubiquitin.
FIG. 7.
FIG. 7.
Regulation and functional consequences of catalase expression or activity differ in myeloid and lymphocytic leukemia. (A) In myeloid leukemia, catalase expression and activity are elevated, leading to decreased ROS levels (light star). Lower ROS levels as a result of catalase contribute directly (solid arrows) to resistance to therapeutic agents, including imatinib and ATO, and have been correlated with cell dedifferentiation (dashed arrow). (B) In lymphocytic leukemia, catalase activity is decreased, resulting in elevated levels of ROS (dark star). Decreased catalase activity correlates (dashed arrows) with elevated lipid peroxidation and DNA damage. DNA damage caused by ROS has been proven to lead to elevated genomic instability (solid arrow). ATO, arsenic trioxide.
FIG. 8.
FIG. 8.
Mechanisms of HO-1 induction in myeloid leukemia. (A) The predominant oncogene in CML is BCR/ABL. This oncogene is noted to increase PI3K signaling, resulting in S6 kinase activity. The downstream result of this activity is degradation of Bach2, resulting in elevated HO-1 expression. BCR/ABL activity also results in upregulation of p47phox, a critical NOX component. p47phox coordinates with NOX2 and Rac1 to produce an increase in ROS. This ROS elevation results in elevated expression of HO-1. The functional results of induction of HO-1 in CML are survival, proliferation, and imatinib/nilotinib resistance. (B) In AML, HO-1 can be induced upon drug treatment. Specifically, treatment with chemotherapeutic agents (cytarabine and daunorubicin) and tumor necrosis factor α (TNFα) has been noted to increase HO-1 expression. Such expression correlates with apoptosis resistance, survival, and chemoresistance in AML cells. PI3K, phosphatidylinositol 3-kinase.
FIG. 9.
FIG. 9.
Activation and regulation of Trx differ between leukemic subtypes. (A) TBP-2 is downregulated in ALL, leading to Trx activity and a decrease in ROS. This decrease has been correlated (dashed arrow) with the proliferation of ALL cells. (B) Trx is elevated in AML, which results in decreased ROS, which in turn has been correlated (dashed arrow) with aggressive disease and shorter relapse interval. (C) In CLL, elevated expression of Trx again results in decreased ROS, which has been noted to decrease apoptosis. (D) TrxR is upregulated in CML, leading to increased Trx reduction. Trx reduction elevates Trx activity, resulting in decreased ROS. This phenomenon has been correlated (dashed arrow) with adriamycin resistance. ROS, reactive oxygen species; AML, acute myeloid leukemia; ALL, acute lymphocytic leukemia; CML, chronic myeloid leukemia; CLL, chronic lymphocytic leukemia; TBP-2, thioredoxin-binding protein 2; Trx-Ox, oxidized thioredoxin.
FIG. 10.
FIG. 10.
Mechanisms of ATO-induced death of leukemia cells. ATO passes through the plasma membrane into the cytosol. Once inside the cell, ATO either (A) directly induces elevations of NOX subunits (p47phox: 400-fold induction; p67phox, Rac2, p40phox, and gp91phox: 2-fold induction), leading to induction of the active NOX complex (in APL) or (B) inhibits the mitochondrial respiratory chain (in AML and ALL). Both scenarios lead to increased ROS generation and subsequent apoptosis of leukemic cells. APL, acute promyelocytic leukemia.
FIG. 11.
FIG. 11.
Potential mechanisms of HDACi ROS induction. HDACi elevate the expression of NOX2, leading directly to increased ROS production. HDACi can also increase gene expression of TBP-2, which binds to and inhibits Trx. Such inhibition directly increases ROS levels and results in Ask1 activity leading to potential mitochondrial apoptosis. Also, specifically noted in leukemic cells, HDACi can promote expression of the proapoptotic BCL-2 family member Bid, leading to alterations in mitochondria and potentiating apoptosis. Bid expression and activity also increase ROS levels, but whether these are a direct result of mitochondrial ROS production or a byproduct of apoptosis remains to be seen. HAT, histone acetyl transferase; Ac, acetylation; BCL-2, B-cell lymphoma 2; HDAC, histone deacetylase; HDACi, histone deacetylase inhibitors.
FIG. 12.
FIG. 12.
Inhibition of the proteasome in leukemia cells leads to elevated ROS levels and cyclically promotes proteasome inhibitor resistance. Proteasome inhibitors (box) can effectively inhibit proteasome activity in leukemia cells. Such inhibition leads to cellular accumulation of ubiquitinated proteins, leading to mitochondrial stress. Ultimately, elevated levels of ROS are induced, which can promote caspase activity and cell death. ROS changes also can promote activation of Nrf2, resulting in increased expression of antioxidant proteins. These antioxidants can block the activity of proteasome inhibitors through direct binding to the inhibitors or decreased ROS production, resulting in resistance to proteasome inhibitor-mediated cell death.

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