Reactive Oxygen Species in Acute Lymphoblastic Leukaemia: History
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Contributor:
Matthew Dun
,
,
Jonathan Sillar
,
Brett Nixon

Acute lymphoblastic leukaemia (ALL) is the most common cancer diagnosed in children and adolescents. Approximately 70% of patients survive >5-years following diagnosis, however, for those that fail upfront therapies, survival is poor. Reactive oxygen species (ROS) are elevated in a range of cancers and are emerging as significant contributors to the leukaemogenesis of ALL. ROS modulate the function of signalling proteins through oxidation of cysteine residues, as well as promote genomic instability by damaging DNA, to promote chemotherapy resistance. Current therapeutic approaches exploit the pro-oxidant intracellular environment of malignant B and T lymphoblasts to cause irreversible DNA damage and cell death, however these strategies impact normal haematopoiesis and lead to long lasting side-effects. Therapies suppressing ROS production, especially those targeting ROS producing enzymes such as the NADPH oxidases (NOXs), are emerging alternatives to treat cancers and may be exploited to improve the ALL treatment. 

  • acute lymphoblastic leukaemia
  • reactive oxygen species
  • oxidative stress
  • NADPH oxidases
  • antioxidants
  • redox homeostasis
  • second messenger signalling
  • oxidative DNA damage
  • resistance
  • oncogenic signalling
  • cysteine oxidation
  • kinase
  • phosphatase

1. Introduction

Acute lymphoblastic leukaemia (ALL) is a heterogeneous malignancy of immature B or T lymphoblasts, which rapidly proliferate in the bone marrow, blood, and some extra-medullary sites such as the spleen and lymph nodes [1]. ALL is the most common form of childhood cancer [2], and although only 20% of ALL diagnoses are diagnosed in adults, four out of five deaths from ALL are in this age group [3]. The overall survival (OS) of children diagnosed with ALL has dramatically improved over the last 40 years. Indeed, the development of multidrug treatment regimens including vincristine [1][4], corticosteroids [5], and asparaginase [6], with most regimens adding an anthracycline [7] (usually doxorubicin or daunorubicin) has reduced treatment resistance, and led to remission rates of greater than 80% [4]. The backbone of ALL treatment is similar in adults; however, they have worse outcomes due to both higher risk disease features at diagnosis and more toxicities associated with therapies [1][4][8]. However, in both populations the early failure of upfront therapies has devastating consequences, with a median 5-year OS of 21% for children [8] and 2% for adults who relapse within their first year of diagnosis [9]. These concerning data highlight the need to continually develop treatments for ALL patients at diagnosis and at disease progression.
A handful of risk factors are associated with ALL including, prenatal exposure to X-rays, postnatal exposure to high doses of radiation and previous treatments with chemotherapy [10], with a genetic predisposition seen in a subset of ALL cases. These include rare genetic and familial cancer syndromes, DNA polymorphisms in non-coding genes and numerous germline variants in coding genes [11]. Chromosomal abnormalities are also common in ALL and include gain or loss of chromosomal content (aneuploidy) and chromosomal rearrangements. Typical chromosomal translocations include, t(9;22) [BCR/ABL1], t(12;21) [ETV6/RUNX1], t(1;19) [TCF3/PBX1], and Mixed-lineage leukaemia (MLL)-rearrangements [1]. Overall consequences of chromosomal abnormalities are the loss of tumour suppressor genes or production of chimeric proteins that dysregulate many cellular processes particularly those that underpin cellular development, differentiation, multiplications, and cell cycle regulation [4]. Recurring somatic and occasionally germline mutations in transcription factors (IKZF1, STAT5) [12][13], tumour suppressors TP53 (including germline variants), CDKN2A [14][15], and signalling pathways genes such as NOTCH1 [16], PI3K/Akt (FLT3, PTEN, PTPN11) [17][18][19][20], JAK/STAT (CLRF2, IL7R, JAK1, JAK3) [21][22] and Ras (BCR/ABL, NRAS, KRAS) [23][24] drive malignant transformation of immature lymphocytes and perturb the function of the body’s immune system. Recurring mutations in signalling genes are strongly associated with pathways that underpin the increased production of reactive oxygen species (ROS); oxidative radicals that induce DNA damage leading to genomic instability and promote leukaemogenesis [25]. However, the roles of ROS in redox signalling and genome instability in ALL remains enigmatic and infantine. In this review, we summarise the known roles that ROS fulfil in the dysfunction of ALL blasts and discuss therapeutic interventions with particular attention given to strategies that reduce ROS production used in combination with established standard-of-care chemotherapies and targeted therapies

 

6. Redox Homeostasis in ALL

ALL cells have evolved several compensatory mechanisms to ensure that ROS production does not induce irreversible DNA damage and cell death [26] (Figure 1). Many of these mechanisms centre on the expression of antioxidant systems with, for example, the gene and protein levels of thioredoxin reductase 1 (TXNRD1), TXN1 and PRDX1 all being elevated in B-ALL cell lines and primary patient samples [27]. Similarly, although H2O2 is usually a key signal in dexamethasone-induced apoptosis, pre-B-ALL cells that display dexamethasone resistance are characterised by overexpression of GSH; yet can be re-sensitised using L-buthionine-(S, R)-sulfoximine (BSO), an inhibitor of GSH synthesis [28]. Furthermore, thymic lymphoma cells that overexpress catalase are also resistant to dexamethasone [29]. As previously noted, manganese superoxide dismutase (MnSOD) overexpression drives H2O2 production and thus sensitises thymic lymphoma cells to dexamethasone via the release of mitochondrial cytochrome c and activation of caspases [30]. Importantly, increased GSH expression is associated with the increased risk of relapse in children diagnosed with ALL [31]. High-level expression of GPx1 is also seen in ALL, influenced by decreased expression of miR-491-5p and miR-214-3p via VPS9D1 antisense RNA 1 [32]. Knockdown of GPx1 reduced proliferation and activated apoptosis, with the VPS9D1 antisense RNA 1 acting as a tumour promoter to increase GPx1 expression and decrease miR-491-5p and miR-214-3p.
Regardless of the subtype, nuclear factor-κB (NF-κB) complexes show constitutive activation in paediatric ALL [33][34]. NF-κB proteins are a family of transcription factors that regulate immune responses to pathogens, inflammation, promote growth and proliferation, and cell development [35]. Indeed, NF-κB transcription factors are responsible for the expression of the ROS producing NADPH oxidase enzymes [36] (discussed in Section 3, Section 5.2, Section 5.7, Section 5.8 and Section 7.2) but can also upregulate the expression of antioxidants (reviewed in [37]). Not only does NF-κB activity increase NADPH oxidase expression and hence ROS production, but ROS regulates the transcriptional activity of NF-κB through degradation of the NF-κB inhibitory protein IκB, promoting nuclear translocation and transcription of κB genes, creating both a feed-forward and positive feedback loop [38][39]. Potentially, the chronic activity of PI3K-Akt signalling driven by recurring ALL associated somatic mutations (BCR/ABL, IL7R/CRLF2), may help to initiate the NF-κB positive feedback loop. Akt activates IκBα kinase (IKK) and p38 MAPK leading to the phosphorylation and degradation of IκB [40]. Loss of PTEN expression further potentiates NF-kB activity through unfettered PI3k/Akt signalling driving the activity of IKK, and further degradation of IκB, supressing apoptosis [41] and driving resistance to doxorubicin [42].
The observations that NF-κB acts an oncogene in ALL, contrasts with pre-B-ALL studies suggesting NF-κB1 is a tumour suppressor. The ratio of phosphorylated and hence nuclear translocated STAT5 to RELA expression (NF-κB transcriptional effector) correlates with B-ALL patient survival and disease remission [43]. Competition between STAT5 and NF-κB for common binding sites increased expression of STAT5 genes including Cyclin D2 and D3 (CCND2, CCND3) and the oncogene MYC (MYC) [43], driving an aggressive form of B-ALL. As there is no doubt that STAT5 plays a critical role in the leukaemogenesis of B and T -ALL, with its activity required for transformation downstream of ALL oncogenes [44][45][46], it is interesting to postulate the direct roles ROS plays in the activity of STAT5 and vice versa. Like NF-κB, STAT5 enhances transcription of the NOX (specifically NOX4). By doing so, STAT5 promotes increased ROS production which acts as a feed-forward loop. However, it is unknown whether the activity of STAT5 plays a direct role in NOX complex activation in ALL. In AML, phosphorylated STAT5 has also been shown to co-localise with Rac1, suggesting a mechanism in which phosphorylated STAT5 promotes ROS production by NOX. Given Rac1 is overexpressed in primary ALL and AML primary blasts compared to controls [47], and pharmacological inhibition of Rac1 is selectively cytotoxic to primary ALL cells and not on normal lymphocytic cells [48], it is indeed possible that the high-level activity of STAT5 in ALL may promote Rac1- induced NOX activity helping to form a feed-forward loop analogous to AML.
There is clear evidence of oxidative dysfunction in ALL. However, to ensure ROS accumulation does not exceed the tipping point and shift from their leukaemogenic roles to induction of regulated cell death pathways, these malignant cells hijack homeostatic mechanisms for survival. The Nuclear factor-erythroid factor 2-related factor 2- NRF2 (NFE2L2), a transcription factor negatively regulated by Kelch-like ECH-associated protein 1 (KEAP1) under basal conditions. ROS mediated redox cysteine PTMs induce conformational changes in KEAP1, leading to the release and subsequent translocation of NRF2 to the nucleus. Within the nucleus, NRF2 binds to antioxidant response element loci located at the promoters of multiple genes that orchestrate cytoprotection through rapid expression of NQO1 (discussed in Section 5.9), combatting oxidative stress and driving cell survival [49][50]. A recent study showed 73% of paediatric ALL patients (22/30) harboured nucleotide changes in genes mapping to the KEAP1/NRF2/NF-κB1/p62 pathway [51]. The significant functional crosstalk between NF-κB and NRF2 suggests that both play important roles in the oxidative dysfunction of ALL cells. It is interesting to note that ALL cells are afforded protection against standard induction chemotherapies via interaction with neighbouring adipocytes [52]. In this regard, daunorubicin treatment of ALL cells has been shown to dramatically upregulate NRF2-mediated oxidative stress response in adipocyte co-cultures and protect ALL cells from genotoxic stress. Such data implies that ALL cells induce oxidative stress in adipocytes through yet an unknown mechanism. Blocking GSH synthesis in adipocytes subsequently re-sensitises ALL cells to daunorubicin, suggesting adipocyte secreted exogenous antioxidants protect ALL cells from chemotherapy [53]. In a similar context, mesenchymal stem cells (MSCs) found in bone marrow release thiols (antioxidant) to protect T-ALL cells from parthenolide induced oxidative stress [54].
In addition to intracellular factors, ALL cells have been reported to make direct contact with the bone marrow stromal cells via tunnelling nanotubes (TNTs); long cylindrical non-adherent actin-based cytoplasmic extensions that play an important role in direct communication and transfer of macromolecules between adjacent cells [55]. Recently, Jurkat ALL cells were reported to directly transfer mitochondria to the bone marrow stromal cells via TNTs upon exposure to chemotherapeutic drugs, thereby reducing ROS induced cellular death [56]. Furthermore, primary patient derived pre-B-ALL cells signal to the bone marrow stromal cells through TNTs, driving secretion of pro-survival cytokines such as interferon-γ–inducible protein 10/CXC chemokine ligand 10 (CXCL10), IL-8, and monocyte chemotactic protein-1/CC chemokine ligand (CCL2) causing resistance to prednisolone [57].
T-ALL switch their metabolic programs in a similar way to normal HSCs when cultured in low oxygen [58]. Reduced mitochondrial activity and cell cycle progression in these low oxygen niches increases glycolysis and lowers their sensitivity to vincristine and cytarabine (cell cycle-related drugs) and dexamethasone, compared with T-ALL cells grown under normoxic conditions [59]. While low oxygen levels suppressed the activity of mTORC1, it increased the activity of HIF1α with the concomitant increase in the expression of HIF1α effector genes such as, VEGF, GLUT3 and CXCR4 to reduce mitochondrial activity and as such ROS levels in ALL [59].
In contrast, B-ALL cells seem to rely more on oxidative phosphorylation and mitochondrial activity than T-ALL [60]. B-ALL cells with reduced NADP/NAD+ ratios were enriched for functional leukaemia-initiating cells (LICs) resistant to cytosine arabinoside (Ara-C) [60]. These cells maintained their oxidative stress levels and resistance to Ara-C through the activation of pyruvate dehydrogenase complex component X (PHDX). Further, Ara-C resistance was attenuated by suppressing oxidative phosphorylation using venetoclax, metformin, and berberine, inhibitors of mitochondrial metabolism in vitro and in vivo [60].
Autophagy is another mechanism that aids leukaemic cells to survive oxidative stress-induced apoptosis. By way of example, ROS have been shown to induce the expression of Beclin-1 (BECN1) (an autophagy related protein with an essential role in autophagosome formation) and increase the removal of injured mitochondria to drive chemotherapy resistance in ALL [61][62]. Importantly, quinacrine (QC) (an anti-malaria drug that potently inhibits autophagy) in combination with vorinostat (a pan-histone deacetylase (HDAC) inhibitor), significantly increased ROS production, which reduced autophagy and caused synergistic apoptosis in T-ALL cells [63].

 

This entry is adapted from the peer-reviewed paper 10.3390/antiox10101616

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