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Abstract

The concept of ‘niche’ has become a focus of attention in hematologic malignancies including acute myeloid leukemia (AML). Similar to normal hematopoietic stem cells, AML cells interact both anatomically and functionally with the stroma within the marrow microenvironment. These interactions have a critical role in the development, progression, and relapse of AML. Chemotherapy resistance is another feature that is at least partially related to AML–stroma interactions. The evidence for safety and efficacy of agents targeting AML–niche interactions is currently limited to preclinical and early phase clinical studies. Examples include CXCR4 inhibitors, hypoxia-inducible agents, and adhesion molecule inhibitors. Agents that target AML–stroma interactions differ from mutation-specific approaches that tend to be limited due to within-individual and between-individual genetic heterogeneity. These agents may be used alone or as chemosensitizers in AML. This novel and rapidly advancing strategy is likely to become an important part of our armamentarium of anti-leukemia treatments in the near future.

Keywords

leukemia microenvironment niche stem cell stroma therapeutics

Introduction

Schofield introduced the concept of ‘niche’ in 1978 to describe the possibility that it is the association between the stem cell and its surroundings that regulates and determines fundamental hematopoietic stem cell (HSC) fate decisions including self-renewal, survival, differentiation, and proliferation [Schofield, 1978]. Since this first introduction, major components of the marrow microenvironment have been identified (Figure 1). In adult marrow, HSCs are primarily located in two specialized compartments: endosteal niche and perivascular niche. The relatively poorly perfused endosteal niche is in close proximity to osteoblasts, and is home to a small proportion of HSCs and a large proportion of early lymphoid progenitors [Lo Celso et al. 2009; Xie et al. 2009; Winkler et al. 2010; Ding and Morrison, 2013]. The perivascular niche, on the other hand, is home to a major proportion of HSCs [Kiel et al. 2005] HSCs interact in this niche with a small population of reticular cells with long processes. These cells have high expression levels of CXCL12 (SDF-1), and were initially called CXCL12-abundant reticular (CAR) cells [Sugiyama et al. 2006]. CAR cells have recently been identified as nestin⁺ mesenchymal stem cells (MSCs) [Greenbaum et al. 2013]. Nestin^brightLepR^-NG2⁺ CAR cells have physical connections to the neighboring HSCs and sympathetic neurons [Méndez-Ferrer et al. 2010; Kunisaki et al. 2013]. Sympathetic autonomic neurons are connected to the sympathetic centers of the central nervous system [Hu et al. 2013]. Nestin⁺ MSCs contribute to bone marrow skeletal formation by differentiating into adipocytes, chondroblasts, and osteoblasts [Méndez-Ferrer et al. 2010; Omatsu et al. 2010].

Figure 1.

Normal bone marrow microenvironment.

HSCs are in anatomic and functional interaction with several stromal elements including both cellular and extracellular elements. MSCs, endothelial cells, osteoblasts, osteoclasts, macrophages, and autonomic neurons are examples of the cellular elements, while the extracellular components include collagen, fibronectin, and laminin fibers (Figure 1).

The AML microenvironment

Acute myeloid leukemia (AML) develops when leukemia stem cells (LSCs) exploit the normal microenvironment and alter it to their own advantage. The corrupted components of the altered niche seem to cooperate with LSCs and maintain the quiescence and survival of LSCs. Also, AML relapse may be facilitated by the anti-apoptotic, anti-differentiation, and proliferative effects of the hematopoietic niche.

In AML xenotransplantation mouse models, AML LSCs are quiescent and engraft within the osteoblast-rich areas of the bone marrow where they are protected from cell cycle-dependent chemotherapy [Ishikawa et al. 2007]. Furthermore, multiple parallel pro-survival and anti-apoptotic signals in AML cells are activated by the stroma [Zeng et al. 2012]. Coculture of AML blasts with stromal cell layers protects AML cells against chemotherapy-induced apoptosis via both soluble factors and cell–cell contact-mediated pathways [Bendall et al. 1994; Garrido et al. 2001]. AML–stroma interactions may also impact resistance to kinase inhibitors. For example, both direct stromal contact and stroma-derived soluble factors are involved in extracellular regulated kinase (ERK)-mediated resistance to FLT3 inhibitors [Sexauer et al. 2012; Yang et al. 2014].

It has been suggested that stromal cells may even have a primary role in initiating AML. Several genetic aberrations have been described in the bone marrow stromal cells of patients with AML [Blau et al. 2007]. These genetic changes are usually distinct from those in AML cells [Blau et al. 2011]. Although highly speculative, a genetically altered niche may provide a permissive milieu for AML to develop and progress. For example, the integrity of normal hematopoiesis depends on the expression of Dicer1 (an RNase III endonuclease essential for microRNA biogenesis and RNA processing) on osteoprogenitors. Deletion of Dicer1 in mouse osteoprogenitors led to myelodysplasia with propensity to evolve into AML. Furthermore, transplanting normal mouse bone marrow cells into Dicer -/- recipient mice resulted in donor-derived myelodysplasia and AML [Raaijmakers et al. 2010].

AML and normal HSC development

LSCs have a similar niche distribution as normal HSCs, allowing for competition between normal HSCs and LSCs for the same niche-related resources. Limited niche availability enables normal HSCs to outcompete LSCs in a cell dose-dependent manner in experimental systems [Boyd et al. 2014].

Also, AML cells alter normal localization and differentiation of HSCs. Rapid leukemia growth expands the intrinsically hypoxic microenvironment [Jensen et al. 2000; Schaefer et al. 2008; Eliasson and Jonsson, 2010], where most HSCs preferentially reside [Chow et al. 2001; Parmar et al. 2007; Winkler et al. 2010]. This has been attributed to the abundance of cytokines in poorly oxygenated areas, which decreases reactive oxygen species production and promotes HSC quiescence and self-renewal [Fiegl et al. 2009]. Transplanted HSCs in leukemic mice migrate away from their healthy niche to the leukemic niche, an effect mediated by stem cell factor (SCF) produced by AML cells. Furthermore, HSCs residing in the malignant niche do not mobilize normally to the peripheral circulation in response to cytokine stimulation. Neutralization of SCF restores the number and mobilization ability of the HSCs [Colmone et al. 2008]. Also, a reversible HSC-to-progenitor differentiation block in the marrow has been demonstrated in a xenograft murine AML model. Normal HSCs in this model failed to produce sufficient progenitors. It is unclear whether the differentiation block is due to the direct effect of AML blasts or is exerted indirectly and via the niche [Miraki-Moud et al. 2013].

The LSC niche has properties that make it distinct from the normal HSC microenvironment. For example, in a murine model of AML, pre-LSCs reside close to osteoblasts on endosteal surfaces. Wnt signaling, a critical mediator of this preferential localization, is predominantly cell-intrinsic in pre-LSCs and LSCs whereas it is niche-derived in normal HSCs, suggesting gain of function in certain pathways that bypass the niche constraints for LSCs [Lane et al. 2011]. Finally, lineage commitment of LSCs is partially dependent upon cues from the microenvironment [Wei et al. 2008].

AML in an inflammatory niche

Similar to solid tumors, AML causes an inflammatory microenvironment; both CD4+ and CD8+ T cells recognizing leukemic-specific antigens have been identified in the marrow, reminiscent of tumor-infiltrating lymphocytes (TILs) [Scheibenbogen et al. 2002]. Although TILs may eliminate some of the LSCs, overall they seem to contribute to leukemia progression. In contrast to solid tumors with their typically complex genomic and (neo)antigenic structure, the majority of the leukemia-specific chromosomal translocations do not give rise to immunogenic neoantigens [Anguille et al. 2012]. This, in addition to the small number of mutations in AML blasts (average of 8–15 single-nucleotide variants per genome in de novo AML), make AML a more difficult tumor for the immune system to recognize and eliminate [Cancer Genome Atlas Research Network, 2013], and for the future generation of neoantigen-specific immunotherapy.

Potentially targetable AML–stroma interactions

CXCR4/CXCL12 signaling

The CXCR4/CXCL12 axis is exploited by AML and is a regulator of cellular migration, mobilization, homing and retention of LSCs during the initiation and progression of leukemia (Figure 1) [Tavor et al. 2004; Katoh and Katoh, 2010]. The interaction between CXCR4 (a G-protein coupled chemokine receptor expressed on the surface of HSCs) and CXCL12 (produced by the marrow stroma and endothelial cells) activates downstream signals resulting in homing of HSCs to the marrow in response to SDF-1 (CXCL12) gradients, HSC quiescence and survival, and regulation of the size of the HSC pool [Sugiyama et al. 2006; Omatsu et al. 2010; Greenbaum et al. 2013]. CXCR4 is expressed also by AML blasts [Mohle et al. 1998]. Signaling pathways activated in AML cells as a result of CXCR4/CXCL12 signaling include the PI3K/Akt and MEK/ERK axes, and downregulation of microRNA let-7a [Zeng et al. 2012; Chen et al. 2013]. While the interaction between CXCL12 and CXCR4 activates the intrinsic pathway of apoptosis in AML cells in vitro [Kremer et al. 2013], a yet undetermined soluble factor secreted by the differentiating osteoblasts protects AML cells against CXCR4/CXCL12-induced apoptosis in vivo [Kremer et al. 2014].

Adhesion molecules: VCAM-1, VLA-4, and E-selectin

Interactions between adhesion molecules and their ligands expressed on HSCs/AML cells and the marrow niche mediate retention of HSCs and AML cells within the marrow. Very late antigen-4 (VLA-4) is a heterodimer expressed on leukocytes and also variably on AML blasts. VCAM-1 (expressed by osteoblasts and endothelial cells) and fibronectin (a component of the extracellular matrix) are two ligands for VLA-4. Under normal circumstances, CXCL12 stimulation results in the activation of VLA-4 on HSCs, leading to activation of the VLA-4/VCAM-1 signaling pathway, and enhancement of HSC adhesion to the endothelial cells followed by their trans-endothelial migration [Peled et al. 2000]. The VLA-4/VCAM-1 axis represents one of multiple redundant pathways which mediate binding of AML cells to endothelial cells allowing for their integration functionally and physically into the vascular niche. Therefore, the endothelium may serve as a site of residual disease. Binding of AML cells to endothelial cells in vitro creates a relatively quiescent phenotype. Despite adopting endothelial cell characteristics and becoming part of the vasculature, AML cells maintain the potential to give rise to leukemia upon transplantation into immunodeficient mice [Cogle et al. 2014].

E-selectin is another cell adhesion molecule which regulates the rolling of leukocytes along the luminal surface of endothelial cells. E-selectin ligand-1 (ESL-1) is expressed on both HSCs and AML blasts, and mediates cell proliferation and exit from quiescence [Winkler et al. 2012]. Mice with homozygous deletion of E-selectin or treated with E-selectin blockers have enhanced HSC quiescence and self-renewal potential, resulting in improved HSC survival following chemotherapy or radiation [Winkler et al. 2012]. The survival of AML blasts is enhanced by their adhesion to the vascular niche via E-selectin ligands and activation of Wnt signaling [Chien et al. 2013]. CD44 (the main receptor for hyaluronic acid) is another ligand for E-selectin on HSCs, and CD44 splice variants are differentially overexpressed on AML blasts [Bendall et al. 2000].

Sympathetic nervous system

The autonomic nervous system is an important component of the normal marrow and converts it to a unit interacting with other tissues as well as the outside environment. Schwann cells encapsulating autonomic nerves in the marrow activate transforming growth factor (TGF)-β, resulting in HSC quiescence. Sympathetic nerve denervation leads to rapid loss of HSCs from the marrow [Yamazaki et al. 2011]. These neurons also contribute to protection of the HSC niche against genotoxic insult [Lucas et al. 2013]. Regeneration of the HSC niche partly depends on circadian egress of HSCs from the marrow regulated by adrenergic signals within the marrow. Circulating HSCs and their progenitors fluctuate in antiphase with the expression of the chemokine CXCL12 in the marrow [Katayama et al. 2006; Méndez-Ferrer et al. 2008].

AML impairs this neural regulation. Ablation of the sympathetic nerves in several mouse models of AML increased marrow infiltration by blasts [Hanoun et al. 2014]. In addition, AML caused sympathetic neuropathy at infiltrated sites (e.g. marrow and spleen), which in turn facilitated progression of disease. Leukemic marrow infiltration also led to the expansion of nestin⁺ MSCs and endothelial cells. The expanded nestin⁺ cells are committed to differentiate to the osteoblastic lineage. These cells express CXCL12 and VCAM-1 at lower levels than normal. Due to a final differentiation block in this process, the numbers of mature osteoblasts is reduced in AML [Hanoun et al. 2014].

Osteoblasts/PTH

Bone turnover is impaired in the leukemic niche. In murine models of AML, osteoblasts are decreased and dysfunctional even before blasts appear in peripheral blood. There is an initial increase in osteoclasts, followed by a decline as the disease progresses to overt leukemia, with the net outcome being mineralized bone loss. Increased levels of the chemokine CCL-3, secreted by AML cells, may contribute to osteoblast dysfunction [Frisch et al. 2012]. In a mouse model of AML, activation of the PTH receptor on osteoblasts accelerated the course of disease, probably via decreased sensitivity to TGF-β1 and expansion of the hematopoietic niche [Krause et al. 2013].

Hypoxia

Hypoxia within the LSC microenvironment has pivotal pro-survival effects on AML cells, and LSCs are known to be better adapted than normal HSCs in such environments. Preferential localization to hypoxic niches minimizes LSC exposure to chemotherapeutic drugs and may limit the recruitment of immune cells with potential anti-leukemic effect [Jensen et al. 2000; Giuntoli et al. 2007]. At the molecular level, hypoxia results in activation of the PI3K/Akt/mTOR pathway and Pim-1 expression [Kornblau et al. 2006; Konopleva and Jordan, 2011]. Another mechanism involves TGFβ1 upregulation due to direct effect of hypoxia-inducible factor (HIF)1α [Zhang et al. 2003], resulting in increased expression of CXCR4 on blasts [Buckley et al. 2000; Katoh and Katoh, 2010]. Interestingly, CXCR4/CXCL12 signaling results in AML cell apoptosis in vitro via the intrinsic pathway [Kremer et al. 2013]. However, the marrow niche protects AML cells against this detrimental effect [Kremer et al. 2014]. The precise mechanism of this protection has not been elucidated. Other studies have suggested that SDF-1-induced signaling through CXCR4 mediates a strong pro-survival signal mediated by the PI3K/Akt pathway [Teicher and Fricker, 2010; Zeng et al. 2012]. These data are further supported by numerous studies demonstrating that antibodies to CXCR4 or small molecule inhibitors of CXCR4 binding to SDF-1 can potently reverse the pro-survival signaling of SDF-1 binding and in some cases directly induce apoptosis of AML cells [Borthakur et al. 2014].

Collagen

Even nonliving components of the niche cooperate with AML cells. Collagen is an important component of the marrow scaffold. High levels of expression of HUIV26 cryptic collagen IV epitope in the marrow results in enhanced migration of AML cells. Remodeled collagen IV is a potent activator of the discoidin domain receptor (a collagen-activated receptor tyrosine kinase). It also activates the Akt pathway, which plays a key role in enhanced migration of AML cells [Favreau et al. 2014].

Clinical progress in targeting AML–stroma interactions

CXCR4/CXCL12 inhibitors

Most of the progress in targeting AML–stroma interactions has been made by development of CXCR4 inhibitors. The rationale behind using CXCR4 inhibitors is to mobilize the leukemic cells out of their protective niches by disrupting the AML–stroma interactions. These agents may also inhibit the pro-survival signals provided to the blasts via CXCR4/CXCL12 signaling. Importantly, CXCR4 expression by AML is prognostic. Patients with higher expression levels of CXCR4 by CD34⁺ cells have shorter survival and higher rates of relapse [Rombouts et al. 2004; Spoo et al. 2007]. In addition, a G801A polymorphism in the CXCL12 gene is associated with higher peripheral blood blast counts and extramedullary disease [Fiegl et al. 2009].

Plerixafor (AMD3100), a small molecule inhibitor of CXCR4, is approved for autologous stem cell mobilization in patients with lymphoma and myeloma when used in conjunction with granulocyte colony-stimulating factor (G-CSF) [DiPersio et al. 2009a, 2009b]. In addition to blocking AML–niche interactions, plerixafor uniquely alters gene expression in both HSCs and AML cells including genes expressed normally during myeloid differentiation [Tavor et al. 2008]. CXCR4 inhibitors have been tested in cell lines, murine models of AML, and in human AML clinical trials. Plerixafor added to cytarabine was superior to cytarabine alone with regards to leukemia burden and overall survival (OS) in a murine acute pro-myelocytic leukemia model [Nervi et al. 2009]. AMD3465 (another CXCR4 inhibitor) mobilized FLT3-mutated AML cells into the peripheral blood. By blocking CXCR4, AMD3465 led to suppression of stroma-activated PI3K/Akt and MEK/ERK pathways in FLT3-mutated AML cells and rendered them more susceptible to cytarabine and sorafenib (a FLT3-inhibitor) in murine xenograft models [Zeng et al. 2009].

The largest body of clinical evidence with CXCR4 comes from plerixafor studies. The safety of the combination using plerixafor in addition to chemotherapy (mitoxantrone, etoposide and cytarabine) was demonstrated in a phase I/II study on 52 patients with relapsed or refractory AML [Uy et al. 2012]. A two-fold increase in AML blast mobilization and a complete remission (CR) and complete remission with incomplete count recovery (CRi) rate of 46% were achieved in this study. In the frontline setting, plerixafor was combined with cytarabine and daunorubicin in a phase I trial. 67% of patients achieved a CR, but 86% experienced an adverse event (AE; including 24% grade 3–4 events) that was at least possibly related to plerixafor [Uy et al. 2011]. A combination of plerixafor with decitabine in elderly patients with newly diagnosed AML resulted in 43% CR/CRi and a median duration of response of 4.5 months [Roboz et al. 2013]. Considering the synergistic effect of plerixafor and G-CSF in stem cell mobilization and the ability of G-CSF to downregulate CXCL12 expression [Petit et al. 2002], studies have also combined the two drugs. A CR/CRi of 28% was achieved using a combination of plerixafor, G-CSF, and sorafenib in a phase I clinical trial of FLT3-mutated relapsed/refractory AML patients [Andreeff et al. 2014]. A 40-fold increase in circulating blasts as a result of mobilization was observed in this study. Hand foot syndrome and diarrhea were two of the adverse effects due to sorafenib.

Ulocuplumab (BMS-936564/MDX-1338) is a fully human IgG4 monoclonal antibody to CXCR4, with half-life longer than plerixafor. It also seems to have direct pro-apoptotic effects on AML cells [Kuhne et al. 2013]. The use of this agent in combination with chemotherapy (mitoxantrone, etoposide and cytarabine) in a phase I clinical trial resulted in a CR/CRi rate of 51% in patients with relapsed/refractory AML. A fivefold mobilization of blasts into the peripheral circulation was observed at day 8 [Becker et al. 2014].

BL-8040 (BKT140) is a selective inhibitor of CXCR4 with prolonged pharmacodynamic effect and direct pro-apoptotic activity against leukemia cells. In a phase I/II clinical trial of patients with relapsed/refractory AML, patients received 2 days of BL-8040 as monotherapy followed by BL-8040 and cytarabine for 5 days. Preliminary results of this study demonstrated safety of all tested doses of BL-8040. Two days of treatment with BL-8040 resulted in 5.14-fold mobilization of AML blasts from the marrow, followed by a 70% decrease in AML blasts in the marrow [Borthakur et al. 2014].

Finally, CX-01 (Cantex Pharmaceuticals) is an O-desulfated heparin with little or no anticoagulant activity. It binds SDF-1 with high affinity effectively blocking the SDF-1/CXCR4 axis. In an early phase clinical trial using CX-01 as a chemosensitizer in newly diagnosed AML patients, 11 of the 12 enrolled patients achieved a morphologic CR (two with minimal residual disease) after one induction. No CX-01-related AEs were observed. CX-01 in this study was given as a bolus followed by continuous intravenous infusion along with induction chemotherapy using cytarabine and idarubicin [Kovacsovics et al. 2015].

It is too early to know whether CXCR4 inhibitors offer additional benefit to intensive or less-intensive chemotherapy in patients with AML. The results in animal models are encouraging and early phase clinical trials have demonstrated safety of these agents in most cases, but the optimal combination and schedule requires additional phase II and eventually randomized phase III trials. Short follow up, patient selection, and small sample size are among factors that limit the generalizability of the results of phase I and II trials. According to the available early phase trials, an important and mechanistically plausible AE of CXCR4 inhibitors is hyperleukocytosis, which should be carefully considered in patient selection in future studies.

Bone marrow hypoxia

TH-302 is a prodrug, which under hypoxic conditions releases the DNA alkylating agent bromo-isophosphoramide mustard. Primary human AML cells that were chemoresistant under hypoxic conditions became sensitive to cytarabine when treated with TH-302. This was manifested by decreased HIF-1α expression, DNA strand breaks, cell cycle arrest, and apoptosis [Portwood et al. 2013]. Clinical experience with TH-302 includes a phase I study in 39 patients with refractory AML [Konopleva et al. 2013]. All patients received conventional chemotherapy in addition to TH-302. Although rapid early cytoreduction occurred in most patients, this was transient and not maintained until the next cycle. Furthermore, although one CR and one CRi were achieved, the patient with a CR had received the investigational agent at a higher dose than was later determined to be the maximum tolerated dose.

VLA-4

The interaction between VLA-4 on AML cells with fibronectin on stromal cells results in the activation of PI3K/Akt/Bcl-2 signaling and, ultimately, resistance to chemotherapy [Matsunaga et al. 2003]. The available clinical evidence for the prognostic value of VLA-4 is in pediatric AML, where high expression of VLA-4 by AML cells was associated with less relapse [Walter et al. 2010]. On the other hand, VLA-4 expression by AML cells does not seem to be prognostic in adults, although increased binding of soluble VCAM-1 via VLA-4 predicts longer OS [Becker et al. 2009]. Resistance to cytarabine in a preclinical model was overcome by a VLA-4-specific antibody [Matsunaga et al. 2003].

Natalizumab (Tysabri) is a humanized VLA-4 monoclonal antibody used for the treatment of autoimmune diseases. In a xenograft murine AML model, animals treated with natalizumab had improved OS compared with control mice [Hsieh et al. 2013]. Natalizumab causes durable HSC mobilization in patients with multiple sclerosis, an effect that last for at least a month after administration [Bonig et al. 2008]. Unfortunately, JC virus-associated progressive multifocal leukoencephalopathy has limited the utility of natalizumab in AML [Bloomgren et al. 2012]. Another VLA-4 blocking agent in clinical development is AS101 which results in redox inhibition of VLA-4 after binding to fibronectin. By causing cytoskeletal changes leading to decreased PI3K/Akt/Bcl2 signaling, AS101 converted chemoresistant AML cells in a mouse xenograft model to chemosensitive cells and prolonged survival of mice receiving chemotherapy [Layani-Bazar et al. 2014].

E-selectin and CD44

AML blasts in relapsed/refractory AML have higher expression of E-selectin than in those with de novo disease, suggesting a role for adhesion of AML cells to the stroma of the vascular niche in relapsed/refractory disease [Chien et al. 2013]. GMI-1271 is a specific small molecule inhibitor of E-selectin. GMI-1271 enhanced the effect of chemotherapy and decreased the leukemia burden in a xenograft model [Chien et al. 2013]. A CD44-specific activating monoclonal antibody blocked engraftment of primary AML cells into NOD/SCID mice and reduced leukemic repopulation. The mechanism involved interference with AML–niche interactions resulting in loss of LSC stem cell properties [Jin et al. 2006].

Conclusions

To date no approach in the treatment of AML has been more effective than traditional chemotherapy. Unfortunately, the outcomes of many patients with high-risk disease treated with chemotherapy remain poor and a significant proportion of patients are unable to receive chemotherapy. There is an unmet need for the development of alternative, more effective, biologically inspired, and better tolerated treatment strategies. AML–niche interactions have a critical role in several aspects of AML, including development, progression, resistance to chemotherapy, and relapse. While targeting a specific mutation in AML cells may result in eradication of the clone(s) or subclone(s) harboring that mutation, the genetic heterogeneity between and within individual patients limits the clinical utility and efficacy of this approach. In contrast, AML–stroma interactions are less cell-specific and therefore, targeting these interactions represents an attractive strategy to overcome the obstacles to effective treatment that are posed by cell–cell and individual–individual heterogeneity. This field is rapidly growing and several new drugs are in various stages of clinical development (Table 1).

Table 1.

Clinical studies of agents targeting AML–stroma interactions.

Regimen	Phase	Patient population	Sponsor	ClinicalTrials.gov identifier	Response
CXCR4 inhibitors
Plerixafor + daunorubicin/cytarabine	I	Untreated, 18–70 years	Genzyme/Sanofi	NCT00990054	CR: 67%
Plerixafor + daunorubicin/clofarabine and daunorubicin/cytarabine	I	Untreated, ⩾60 years	Cardiff University	NCT01236144
Plerixafor + G-CSF, mitoxantrone/etoposide/cytarabine	I	Relapsed/Refractory, ⩾18 years	Washington University	NCT00906945
Plerixafor + decitabine	I	Untreated, ⩾60 years	Weill/Cornell University	NCT01352650
Plerixafor + cytarabine/etoposide	I	Relapsed/Refractory, 3–30 years	Emory University	NCT01319864
Ulocuplumab + mitoxantrone/etoposide/cytarabine	I	Relapsed/Refractory, ⩾18 years	Bristol-Myers Squibb	NCT01120457
CX-01+ idarubicin/cytarabine	I	Untreated, 18–80 years	Cantex	NCT02056782
Plerixafor + mitoxantrone/etoposide/cytarabine	I/II	Relapsed/Refractory	Washington University	NCT00512252	CR/CRi: 46%
Plerixafor + clofarabine	I/II	Untreated, ⩾60 years	MD Anderson	NCT01160354	ORR: 43%
Plerixafor + fludarabine/idarubicin/cyarabine/G-CSF	I/II	Second line induction, ⩽65 years	PETHEMA	NCT01435343
Plerixafor + busulfan/fludarabine/thymoglobulin	I/II	Allo-SCT, 18–65 years	MD Anderson	NCT00822770
BL-8040 + cytarabine	IIa	Relapsed/refractory, 18–75 years	BioLineRx	NCT01838395
VLA-4 inhibitor
AS101 + chemotherapy	II	Untreated, ⩾60 years	BioMAS	NCT01010373
E-selectin inhibitor
GMI-1271 + mitoxantrone/etoposide/ cytarabine	I/II	Relapsed/Refractory or untreated, ⩾60 years	GlycoMimetics	NCT02306291
Hypoxia-inducible agents
TH-302	I	Relapsed/Refractory, ⩾18 years	Threshold Pharmaceuticals	NCT01149915

Allo-SCT, allogeneic stem cell transplantation; AML, acute myeloid leukemia; CR, complete remission; CRi, complete remission with incomplete count recovery; G-CSF, granulocyte colony-stimulating factor; ORR, overall response rate.

Barriers to success in this field include potential additional toxicity of investigational agents, limitations in translation of animal studies to humans, unknown optimal combinations and treatment schedules, lack of large phase II or III clinical trials, and perhaps most importantly, our still limited knowledge of the basic biology of AML. Among the agents investigated to date, CXCR4 inhibitors have been most promising. However, there is a long way to go before these agents can become a part of treatment for patients with AML. Since AML primarily affects the elderly, and is a rapidly proliferating neoplasm, an ideal agent should be well tolerated by the typical AML patient (elderly with a number of comorbidities and decreased organ function) and augment the effect of conventional chemotherapy. Alternatively, niche-directed agents may be used as a replacement for one or more components of combination chemotherapy in frail patients. Finally, they may be combined with less intensive treatments such as hypomethylating agents in patients who would not tolerate intensive cytotoxic therapy. Given the rapidly proliferative nature of AML and its particular aggressiveness and treatment resistance in the elderly, targeting the niche as the sole anti-leukemia strategy is unlikely to be successful and will probably not replace conventional chemotherapy when curative intent treatment is the goal.

A potential unexplored area for future research is targeting AML–niche interactions in patients in remission after conventional chemotherapy. Residual LSCs are thought to be responsible for the majority of relapses in this setting. Targeting the microenvironment may bring LSCs out of their protective and immunosuppressive niches and result in eradication of AML. Safety of targeting agents in remission settings should be the focus of special attention when designing clinical trials because chemotherapy alone can cure a large number of patients. Given the ubiquitous nature of tumor–microenvironment interactions, lessons learned from other hematologic malignancies may be applicable or useful in AML. The results of ongoing and future studies using these agents will determine whether targeting AML–niche interactions can result in improved outcomes in patients with AML.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare that there is no conflict of interest.

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Targeting the leukemia–stroma interaction in acute myeloid leukemia: rationale and latest evidence

Abstract

Keywords

Introduction

The AML microenvironment

AML and normal HSC development

AML in an inflammatory niche

Potentially targetable AML–stroma interactions

CXCR4/CXCL12 signaling

Adhesion molecules: VCAM-1, VLA-4, and E-selectin

Sympathetic nervous system

Osteoblasts/PTH

Hypoxia

Collagen

Clinical progress in targeting AML–stroma interactions

CXCR4/CXCL12 inhibitors

Bone marrow hypoxia

VLA-4

E-selectin and CD44

Conclusions

Footnotes

Funding

Conflict of interest statement

References