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P.M. Le et al.
inhibitors, such as AMD3100 (plerixafor) and AMD3465, show anti-leukemic effects only synergisti- cally with chemotherapy and their action is rather tran- sient, a second generation that has potential as monotherapy is emerging.78,79 Of note, the clinical bene- fit of CXCR4 blockade could be further optimized given the role of differentiating osteoblasts in shielding AML cells from CXCL12-mediated apoptosis in hypoxia.12 Though such induction of apoptosis80 is controversial,79,81- 83 it cannot be excluded that the interplay between hypoxia-mediated protection of leukemic cells typically found in AML BM84,85 and niche components may tip the balance between CXCL12-mediated pro-survival and apoptosis. This possibility is noteworthy given CXCR4 is a well-established target of HIF-1α, and therefore hypoxia.86 The role of HIF-1α in survival and mainte- nance of CML has also been described.87 The Bonnet group found that HIF-2α, another factor that is regulated by hypoxia, plays a crucial role in regulation of the long- term re-populating ability of CD34+ umbilical cord blood cells. In addition, their data demonstrate that inhibition of HIF-2α in primary AML cells inhibits their prolifera- tion and sensitizes them to endoplasmic reticulum stress-induced apoptosis by upregulation of reactive oxygen species.85
Similarly, chemosensitization and reduced AML engraftment could be achieved in mouse models with the use of CD44 specific antibody88 and VLA-4 blocking agents, such as natalizumab89 and AS101.90 Extra- medullary BM models by Chen et al.91 and Jacamo et al.92 demonstrated that AML and stromal cells interact via VLA-4 and VCAM1 to activate downstream NFkB signal- ing in both cell types. Blockade of these interactions resulted in inhibition of stroma-induced chemoresistance in AML cells.91,92 Besides, antagonizing these adhesion molecules has been found to relieve differentiation block in blasts,88 a clinical benefit also seen when epigenetic modifiers93 or FLT3 and IDH1/2 inhibitors94,95 were used to treat AML. This mobilizing approach, while preferen- tially mobilizing AML cells, carries the risk of moving HSCs out of their protective BM niche, among other adverse effects.96-98 Further randomized trials are needed to determine whether targeting AML homing axes is safe and how to optimize this chemosensitizing approach without impairing normal hematopoiesis.
There has been growing evidence to indicate another promising strategy: to target osteoblast function. Leukemia-stroma contact potentiates osteoblast differen- tiation in MSCs, which counteracts apoptogenic cues and promotes proliferative signals from the microenviron- ment to leukemic cells.12,50,55 It has also been shown that abnormal signaling pathways and crosstalks that take place specifically in osteoblasts could induce or aggravate AML phenotype.8,38 Manipulating signals from osteolin- eage cells would, therefore, render the osteogenic niche hostile to AML cells and abrogate the feedback loop fuel- ing their perpetual life cycle. Indeed, modulation of mature osteoblast numbers by inhibiting gut-derived serotonin synthesis results in leukemia regression, pro- viding a 'proof of concept' for this approach.65
The fact that stage-specific osteolineage cells have dis- tinct functions and may differentially regulate normal and malignant hematopoiesis makes them an even more attractive target, especially with regard to their involve- ment in pleiotropic signaling pathways that support
HSCs, such as Notch or TGF-β. For example, despite already being known for its tumor-suppressor role in AML,99,100 Notch activation has been reported to be leuke- mogenic when synergizing with activating β- catenin/FoxO signaling in Col1a1+ pre-osteoblasts.38 This observation suggests targeting FoxO signaling in pre- osteoblasts may be beneficial to patients with constitu- tive activating β-catenin mutation. As the effects of myeloid leukemia on cell differentiation along the osteo- lineage unfold, more leukemia modulators might be iden- tified, and these will facilitate patient stratification and prevent treatment failure.
Restricting osteogenic capacity of MSCs could also be a therapeutic option. This strategy potentially limits the OPN reservoir of the BM, further preventing AML cells from hid- ing in the osteogenic niche and evading chemotherapy. Maintaining the primitive MSC pool via β2- and β3-adren- ergic agonists has shown multiple advantages in managing AML and MPN: rescuing healthy HSCs in the osteogenic niche with HSC maintenance factors and preventing LSCs from crowding out these normal residents.49,101 Studies have further shown that the bone surface and periarteriolar region are prone to inflammation during the early stage of osteogenic niche remodeling.39,56 This can be ameliorated by blocking receptors of pro-inflammatory cytokines, e.g. via CCL3 receptor antagonists.
Alternatively, promoting adipocyte differentiation of MSCs has been demonstrated to be a viable strategy to improve disease management by rescuing at least the generation of myeloid-erythroid lineages.51 However, the long-term efficacy of this pro-adipogenesis therapy remains to be tested given the debatable evidence about the role of adipocytes in AML seen so far. Different groups reported on adipocyte re-programming in which AML blasts exploit these energy reservoirs through lipol- ysis to fuel uncontrolled expansion.102-104 On the other hand, Lu et al.105 only found a statistically significant cor- relation between AML patients’ poor prognosis and an increase in small adipocytes, but not the decrease in large- or medium-sized ones. This finding suggests that lipid transfer may not be the only mechanism through which adipocytes aggravate leukemia burden. It cannot be excluded that, as previously shown in acute lymphoblas- tic leukemia,106,107 adipocytes may acquire a chemoprotec- tive role in the setting of AML.
Recent discoveries provide evidence that mitochondria are transferred from BM stromal cells to leukemia cells which influence leukemia progression.108 These studies demonstrate that mitochondria are transferred via tunnel- ing nanotubes (TNTs) or extracellular vesicles resulting in enhanced ATP production through increased oxidative phosphorylation (OXPHOS) which translates into higher drug resistance in AML cells and relapse after chemother- apy.109,110 Therefore, inhibition of mitochondrial transfer by targeting TNT formation or inhibiting OXPHOS is currently being considered as novel therapeutic strategies in AML therapy.
Conclusions and emerging questions
Findings on BM stroma-mediated chemoprotection in AML since the early 2000s have paved the way for a wave of new insights into leukemia-BM niche interac- tions, hence re-defining the paradigm of leukemic devel-
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haematologica | 2018; 103(12)