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Editorials
hydroxycarbamide. A trend was also observed towards reduction in megakaryocyte cluster formation and decrease in numbers of large megakaryocytes with staghorn-like morphology, both cardinal features of MPN. Possible confounding factors are that the participants had established MPN with a median time between MPN diag- nosis and trial registration of 3.6 years (range 1.6-8.6 years) and received a relatively short duration of therapy. It is possible that longer exposure to mirabegron, which was well tolerated, and considering its use earlier in the disease course may have demonstrated different results since potentially the chronicity and degree of increase in nestin+ MSC may be paramount in ultimately modulating the clin- ical phenotype. Mirabegron itself, as noted above, is a less potent agent and may have additional effects when com- pared to BRL37344, which was used in the murine work.
+ Moreover, although significant increases in Nestin MSC
were seen, this was limited to those patients not receiving hydroxycarbamide, an agent that most likely affected MSC senescence.
As we begin to explore the complex BM HSC-neuro- stromal interaction through niche targeting therapies, such as that described in the novel study described above, sig- nificant thought needs to be given to the timing of such therapies within the disease course and that logical sequencing / dual agent approaches are considered when targeting of this axis is contemplated. For example, the JAK inhibitor ruxolitinib has been shown to abrogate MSC- growth and an ability to secrete MCP and IL-6 which could potentially be beneficial through downregulation of pro- inflammatory MSC, yet it is unknown what effect prior or concurrent JAK inhibitor therapy would have on β3 adren- ergic agonist mediated-increases in Nestin+ MSC.24 It is increasingly evident, however, that strategies with the abil- ity to break through the self-perpetuating inflammatory and pro-oncogenic MPN microenvironment are required. Potential combination approaches with drugs acting on this axis to explore include the human pentraxin-2 protein analog PRM-151 (Promedia Pharmaceuticals), which may potentially synergistically reduce fibrosis, or with interfer- on, which may ‘switch on’ mutant-HSC-directed immune responses. Both of which are being assessed as single agents and in combination with ruxolitinib (reviewed by Harrison and McLornan25). Furthermore, an additional ben- efit of focusing on the stem cell niche could generate a sur- rogate marker of disease response that would facilitate more rapid evaluation of niche-targeting therapies in the clinical arena. Surrogate markers of disease response mov- ing beyond the blood count, symptoms and spleen are urgently required in this field. An enhanced understanding of the role of the neural network within the MPN niche and how this can be successfully modulated will accelerate the design of such synergistic therapeutic approaches and help the field to move forward. This work from Méndez- Ferrer and Skoda is also an inspiration in following the aca- demic trail from bench to bedside.13,14,17,23
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