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Current Opinion in Hematology:
doi: 10.1097/MOH.0b013e3283545615
HEMATOPOIESIS: Edited by Hal E. Broxmeyer

Selective treatment of mixed-lineage leukemia leukemic stem cells through targeting glycogen synthase kinase 3 and the canonical Wnt/β-catenin pathway

Fung, Tsz K.a,*; Gandillet, Arnauda,b,*; So, Chi W.E.a

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aLeukaemia and Stem Cell Biology Group, Department of Heamatological Medicine, The Rayne Institute, King's College London

bCancer Research UK Haematopoietic Stem Cell Group, London Research Institute, London, UK

*These authors contributed equally to this work.

Correspondence to Chi W.E. So, Leukaemia and Stem Cell Biology Group, The Rayne Institute, King's College London, 123 Coldharbour Lane, London SE5 9NU, UK. Tel: +44 20 7848 5888; e-mail:

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Purpose of review: Leukemia carrying mutation of the mixed-lineage leukemia (MLL) gene is particularly refractory to current treatment, and is associated with frequent relapse. We will review the biology of MLL leukemia, and explore the potential of targeting multiple signaling pathways deregulated in MLL leukemic stem cells (LSCs).

Recent findings: Glycogen synthase kinase 3 (GSK3) plays a critical role in mediating Hox/MEIS1 transcriptional program and its inhibition shows promise in suppressing leukemia carrying MLL fusions or aberrant Hox expression. However, recent evidence indicates that GSK3 inhibition can be overcome by hyperactivation of the canonical Wnt signaling pathway in MLL LSCs, whereas suppression of β-catenin resensitizes MLL LSCs to the GSK3 inhibitor treatment. These results suggest a differential GSK3 dependence in different subsets of leukemic populations during disease development.

Summary: On the basis of the results from preclinical model studies, a combination treatment targeting both GSK3 and the canonical Wnt signaling pathway emerges as a promising avenue to eradicate MLL LSCs. Future effort in identifying the key tractable components along these signaling pathways will be critical for the development of effective inhibitors to target this aggressive disease.

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Acute myeloid leukemia (AML) is a group of heterogeneous diseases originating from hematopoietic stem cells (HSCs) or early myeloid progenitors that upon genetic mutations and/or epigenetic alterations can be converted into preleukemic stem cells (pre-LSCs) and subsequently LSCs [1–3]. Conventional chemotherapy leads to a complete remission in about 70% of AML cases; however, most of them relapse and only 30% of patients can achieve a long-term remission [4]. This observation is consistent with the hypothesis that there are rare populations of cancer stem cells (CSCs) that are refractory to the standard treatment and are capable of reinitiating the disease during relapse [5▪]. Although the CSC model is unlikely to be universal to all tumor subtypes, which can have vastly different frequency of CSCs depending on the nature of the oncogenic events and tumor environments, emerging evidence revealing a significant number of tumors including leukemia closely following the model indicates a recurring and critical theme in cancer biology. Understanding the molecular regulation and pathways that govern the homeostasis (self-renewal/proliferation) of LSCs can provide important clues to direct future therapeutic strategies targeting this important pool of drug-resistant leukemic cells. Among all AML subtypes, leukemia carrying mutation of the mixed-lineage leukemia (MLL) gene is particularly resistant to treatment [6]. Such MLL rearrangements are associated with poor prognosis and occur in about 70% of infant leukemias, 10% of adult AML, and 50% of secondary leukemias associated with topoisomerase II treatment.

In the present review, we will discuss: the role and regulation of Hox/MEIS activity in MLL leukemia, the signaling pathways that may be critical for MLL leukemogenesis and drug resistance, and the potential strategies for the eradication of MLL LSCs by targeting such pathways, especially via glycogen synthase kinase 3 (GSK3) and β-catenin inhibition.

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As a result of chromosomal translocation, MLL forms chimeric fusions with more than 60 different fusion partners, which will either provide homodimerization/oligomerization domains or transactivation effector domains to the truncated MLL to activate the expression of their downstream targets, including Hox genes [7]. MLL fusions aberrantly recruit histone-modifying enzymes, such as H3K79 histone methyltransferase DOT1L [8] and H4R3 protein arginine methyltransferase PRMT1 [9], to initiate a stem cell-like transcriptional program that enhances or even confers self-renewal properties to targeted HSCs or short-lived progenitors, respectively. Suppression of these histone-modifying enzymes by either knockout or short-hairpin RNA approaches significantly inhibits MLL transformation, although the development of small molecule inhibitors efficiently targeting these enzymes is still at its infancy [10]. Recently, two additional proteins involved in histone modifications, the BET family of acetyl-lysine recognizing protein [11▪] and the chromobox 8 protein [12], have been identified as critical molecules required for MLL transcriptional activity. Moreover, BET inhibitors are already available and have exhibited good efficacy in suppressing leukemic growth [11▪]. These results clearly indicate that transcriptional deregulation is key for MLL leukemogenesis. Some of the most important downstream targets of MLL fusions involved in leukemic transformation include Hox cluster genes such as Hoxa7, Hoxa9, Hoxa10, and Hoxb4, and nonHox genes such as c-Myb, CBX2, and MEIS1. Among all the Hox, Hoxa9 has been shown as an essential target for leukemogenesis mediated by certain MLL fusions [13,14], and is independently identified as one of the most significant single prognosis factors for human AML associated with treatment failure [15]. In cooperation with MEIS1, Hoxa9 is sufficient to transform primary mouse bone marrow cells and induce AML [16]. Hoxa9 is also fused with NUP98 in a subset of AML that is refractory to standard chemotherapy [17]. Together, these studies strongly suggest that activation of Hox genes, in particular Hoxa9, plays critical roles in myeloid leukemogenesis and can potentially be exploited for therapeutic intervention.

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Recent evidence indicates that MLL/Hox activity can be modulated by differentially regulated, although interdependent, signaling pathways. In this section, we discuss how GSK3 regulates Hox/MEIS1-mediated transcription, and the role of Wnt/β-catenin pathway in MLL transformation and drug resistance (Fig. 1).

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Glycogen synthase kinase 3 inhibitors in mixed-lineage leukemia

GSK3 acts on a wide spectrum of substrates and exhibits diverse functions in tissue development including neurogenesis, cardiovasculogenesis, and hematopoiesis. Its aberrant activation is linked to tumorigenesis in colon [18] and pancreatic [19] cancers. The molecular mechanism by which GSK3 inhibition suppresses MLL activity has been extensively studied in the years [20▪▪,21]. In these studies, suppression of GSK3 activity specifically inhibited the proliferation of leukemic cells transformed by MLL fusion or its major downstream effectors, Hoxa9/MEIS1, suggesting that GSK3 activity is linked to leukemogenesis through Hox/MEIS pathway [20▪▪]. Further biochemical analyses revealed that GSK3 phosphorylated Creb on serine residue 129, and promoted the association of Hox transcription complex with its coactivators Creb-bind protein and Torc. Inhibition of GSK3 kinase activity by small molecule inhibitors prevented serine phosphorylation of Creb and abolished its physical association with coactivators to Hox transcription complex [20▪▪]. Overexpression of Creb significantly shortened the latency of MLL-AF6-mediated leukemia in mice. Conversely, knockdown of Creb or expression of a nonphosphorylable S129A mutant disrupted active Hox transcription complex and suppressed leukemic colonies formation by MLL-AF6-transformed cells, demonstrating that Creb phosphorylation by GSK3 is a crucial step in MLL fusion-mediated leukemogenesis [20▪▪]. In addition to Hox/MEIS-mediated transcription, GSK3 inhibition also activates p27 expression and provokes cell cycle arrest in G1 phase [21] (Fig. 1a). Although the molecular mechanism of GSK3-mediated suppression of p27 in leukemia remains unclear, selective inhibition of GSK3 shows promising results in suppressing leukemia driven by MLL mutation or Hox/MEIS.

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Glycogen synthase kinase 3 inhibitors in other myeloid leukemias

GSK3 inhibition is also effective for the treatment of other myeloid leukemias [22,23]. In-vivo administration of a selective GSK3 inhibitor, BIO, suppressed tumor formation by K562 cells in immunodeficient recipient mice, and BIO treatment of primary AML cells prior to transplantation also impaired their repopulating ability [23]. The potential use of GSK3 inhibitors on a wide spectrum of AML was further demonstrated in a recent genetic and chemical genomic screen that identified GSK3α as a potential target in multiple AML subtypes, although future studies using primary human samples and mouse models are needed to further validate the findings [24▪]. Interestingly, inhibition of GSK3 by in-vivo administration of a small molecule inhibitor activated Wnt/β-catenin and enhanced long-term repopulation of human and murine HSCs, which in turn improved the survival of lethally irradiated recipients [25]. Together, these results suggest that GSK3 inhibition may be able to target leukemic cells while enhancing normal stem cell functions.

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Glycogen synthase kinase 3 as a tumor suppressor

Given the function of GSK3 in suppressing the canonical Wnt/β-catenin signaling pathway by promoting ubiquitin/proteasome-dependent proteolysis of β-catenin [26], it is not surprising that GSK3 can also act as a tumor suppressor. This has been observed in breast and skin cancers, in which enforced expression of kinase-dead GSK3β promotes tumorigenesis, whereas ectopic expression of either wild type or the constitutively active form of GSK3β suppressed tumor growth [27,28]. Therefore, in certain tumors, GSK3 inhibition may actually promote oncogenesis.

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The canonical Wnt/β-catenin pathway in acute myeloid leukemia

Interestingly, β-catenin, previously demonstrated to govern blast transformation of chronic myeloid leukemia (CML) [29,30], has been recently identified as an essential molecule for the development of LSCs driven by MLL fusions or Hox/MEIS [31▪,32▪▪]: Hoxa9/MEIS1 was capable of transforming murine HSC-enriched populations (LinSca-1+c-Kit+ cells) but failed to transform granulocyte–macrophage progenitors (GMPs), a compartment in which β-catenin is downregulated. Whereas forced expression of a constitutively active form of β-catenin per se was not leukemogenic, it could resurrect the transformation ability of Hoxa9/MEIS1 in GMP [32▪▪]. Conversely, genetic or pharmacological suppression of β-catenin expression inhibited leukemogenic transformation mediated by MLL fusions or Hoxa9/MEIS1, revealing its essential function in leukemic transformation [31▪,32▪▪]. In human AML, elevated β-catenin expression is also associated with high relapse rate and poor overall survival [33,34]. Elevated expression of β-catenin enhanced blast-replating efficiency [33]. Silencing of β-catenin impaired engraftment potential of HL60 and Fujioka AML cell lines [35,36] and reduced the frequency of long-term culture initiating cells from some primary AML samples [31▪,35]. Together, these data reveal a critical role of β-catenin in mediating myeloid transformation.

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β-catenin and drug resistance in myeloid leukemia

In addition to development of leukemia, the canonical Wnt/β-catenin pathway also plays a key role in mediating drug-resistant properties in myeloid leukemia. In a murine model of CML, the inhibition of BCR-ABL leads to selection of LSC clones with elevated expression of β-catenin that are resistant to the treatment [37]. More strikingly, β-catenin may also contribute to GSK3 inhibitors resistance in MLL leukemia. As summarized in Fig. 2, MLL pre-LSCs with a low level of β-catenin remain sensitive to GSK3 inhibitor treatment. However, as the disease progresses, the canonical Wnt/β-catenin pathway gets hyperactivated in LSCs, which become resistant to GSK3 inhibitors [31▪]. The mechanism of β-catenin activation from pre-LSCs to drug-resistant LSCs is still obscure and it may also involve other factors. Importantly, suppression of β-catenin restored the GSK3 inhibitor sensitivity to MLL LSCs both in vitro and in vivo[31▪], unveiling its critical functions and a potential novel avenue by targeting β-catenin for treatment of drug-resistant MLL LSCs (Fig. 2).

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Targeting of LSCs is not a novel idea and represents one of the holy grails in leukemia research. The recent efforts to identify essential molecules for LSCs functions have provided a first glimpse of hope in achieving this goal. For aggressive forms of leukemias like MLL/Hox-mediated leukemias, inhibition of Creb phosphorylation by GSK3 inhibitors has shown good efficacy. However, inhibition of GSK3 alone (Fig. 1b) may only be effective when leukemic cells solely rely on this single pathway [20▪▪,31▪]. In this regard, the study by Yeung et al.[31▪] showed that MLL leukemic cells were initially sensitive to GSK3 inhibitors but then became resistant after primary transplantation. This suggests that GSK3 inhibition can be ineffective to target certain LSCs that have acquired additional genetic/epigenetic alternations that allow them to escape from GSK3 inhibition by activating alternative pathways such as the canonical Wnt signaling. In fact, activation of β-catenin activity is a likely undesirable side product of GSK3 inhibition, which in turn promotes cell proliferation and drug resistance through enhanced expression of its downstream targets such as cyclin D1, c-Myc, and survivin. Interestingly, Hoxb9 has recently been identified as a critical transcriptional target of Wnt/TCF in lung adenocarcinoma tumor metastasis [38]. Suppression of β-catenin may also inhibit Hox expression that is crucial for leukemogenesis, although further experiments are required to investigate whether a similar molecular regulation also takes place in leukemia. Thus, in order to counteract these adverse side effects associated with reactivation of the canonical Wnt signaling, a combined inhibition of GSK3 and β-catenin is proposed (Fig. 1c). Indeed, β-catenin is a particularly attractive target as it is deregulated in multiple leukemia subtypes and is largely dispensable for normal hematopoiesis [39,40]. Its activation is also directly related to drug-resistant properties observed in different cancers, which may share common mechanisms [41,42]. For these reasons, there are already a number of small molecule inhibitors that target various components of the canonical Wnt signaling pathway, for example, extracellular ligand/receptor binding, stability of β-catenin, or interaction of β-catenin with coactivators [43–45]. Unfortunately, most of these inhibitors targeting regulators of β-catenin will likely also affect other pathways, although it may not necessarily impair their therapeutic virtues. Thus, further efforts in identifying existing or novel inhibitors that specifically target β-catenin in combination with GSK3 inhibitors for the treatment of AML stem cells will be of great interest.

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Given the heterogenic nature and genetic/epigenetic variegation of clonal architecture of LSCs [46▪], targeting multiple molecules or pathways is likely required to eradicate LSCs. A recent example is the combined inhibition of BCR-ABL by imatinib together with a SIRT1 inhibitor that activates p53 to eliminate CML stem cells [47▪,48]. For MLL leukemia, it is possible to simultaneously target critical transcription cofactors recruited by the fusions such as DOT1L [49▪], PRMT1 [9], and BET [11▪], which have more rigid structural domains as docking sites for small molecule inhibitors. Of note, Bmi1 [50▪,51], Hedgehog [52,53] phosphatase and tensin homolog (PTEN) [54], and Notch [55,56] pathways have also been identified to play critical roles for LSCs functions. Inhibitors against various components of these pathways are being developed, and mechanistic target of rapamycin inhibitors have already been used in a preclinical model and show good efficacy in suppressing leukemia with PTEN deletion [57]. Obviously, application of these inhibitors has to be highly selective and determined empirically on the basis of the driver mutations identified in the LSCs. Recent evidence indicates that although Bmi1 plays a critical role for various CSCs, it is largely dispensable for MLL leukemia and suppression of Bmi1 function does not affect the function of MLL LSCs [50▪]. This further highlights the importance of future efforts in dissecting the molecular pathways that are deregulated in LSCs specific to the disease for designing effective cancer therapies.

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T.K.F. is a Lady Tata Memorial Trust Fellow. A.G. is a London Research Institute Cancer Research UK Fellow. C.W.E.S. is supported by Leukaemia and Lymphoma Research (LLR) UK, Kay Kendall Leukaemia Fund (KKLF), Medical Research Council (MRC), and the Association for International Cancer Research (AICR).

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Conflicts of interest

There are no conflicts of interest.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 338).

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glycogen synthase kinase 3; Hox; leukemic stem cells; mixed-lineage leukemia; Wnt/β-catenin

© 2012 Lippincott Williams & Wilkins, Inc.


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