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Exploitation of the neural-hematopoietic stem cell niche axis to treat myeloproliferative neoplasms
Naoimh Herlihy, Claire N Harrison and Donal P McLornan
Department of Haematology, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK E-mail: CLAIRE HARRISON - claire.harrison@gstt.nhs.uk
doi:10.3324/haematol.2018.211896
Myeloproliferative neoplasms (MPN) originate from a population of hematopoietic stem cells (HSCs) with- in the bone marrow (BM) that undergo clonal expan- sion as a result of factors both intrinsic and extrinsic to the cell. They are characterized by progressive marrow fibrosis, hetero- geneous symptomatology, extramedullary hematopoiesis, splenomegaly, a propensity to both hemorrhage and thrombo- sis, and an inherent risk of transformation to acute myeloid leukemia (AML). Recently, there has been an increasing focus on the role of the BM HSC niche in MPN development and disease maintenance.1 This niche encompasses complex cellu- lar and signaling networks with multiple interactions and ‘cross-talk’ between HSC, mesenchymal cells (MSC), perivas- cular cells identified as chemokine (C–X–C motif) ligand 12 (CXCL12)-abundant reticular (CAR) cells, osteolineage-derived cells and sinusoidal endothelial cells, amongst others1-3 (Figure 1). Importantly, the acquisition of gain-of-function mutations such as JAK2-V617F by MPN HSCs or other cells can result in an alteration of the niche to favor clonal expansion at the expense of background normal HSCs.4 For example, Zhan et al. recently suggested that JAK2-V617F mutant endothelial cells in the vascular niche promote clonal expansion of JAK2-V617F HSCs at the expense of wild-type progenitors.5 In chronic myeloid leukemia (CML), one study found BCR/ABL trans- genic mice create a self-reinforcing leukemic niche that impairs normal hematopoiesis, favors leukemic stem cell function and contributes to development of BM fibrosis by stimulating MSCs to overproduce osteoclastic stem cells.6 Conversely, there is also mounting evidence that targeted disruption of the HSC niche may result in development of MPN, for example defective Notch activation7 and ablation of the retinoic acid receptor gamma8 and retinoblastoma genes9 have been evaluated in murine models, suggesting that genetic mutations in the niche itself can also drive the malignant process. Little was known about the role of the MSC population in MPN-pathogenesis and maintenance and data were often conflicting. Avanzini et al. described how MPN-BM-derived MSC exhibited decreased proliferative and osteogenic capacity whereas Martinaud et al. suggested an enhanced and persistent increase in osteogenic abilities coupled with an altered secretome and transcriptome in primary myelofibrosis (PMF)-derived BM-MSC.10,11 More recently, Ramos et al. demonstrated that BM-MSC derived from JAK2-mutated MPN patients favored maintenance of clonal hematopoietic cells.12 Targeting of this population, in particular increasing the ‘beneficial’ MSC subgroup, is hence of potential interest.
Nearly a decade ago, Méndez-Ferrer et al. originally described how Nestin-positive(+) MSC are essential compo- nents of the HSC niche, containing all of the BM colony-form- ing-unit fibroblastic activity and having the ability to function as so-called ‘niche-forming’ cells.13,14 Nestin is a type VI inter- mediate filament protein and functions as a major component of the cytoskeleton. Méndez-Ferrer et al. described that cyclical
HSC trafficking is regulated by noradrenaline release via the sympathetic nervous system (SNS), transmitted to niche stro- mal cells by the beta(β)(3)-adrenergic receptor, resulting in reduced nuclear Sp1 transcription factor and downregulation of CXCL12. There is a close association between so-called Nestin+ MSC and adrenergic nerve fibers of the SNS and this is believed to control HSC maintenance, egress and functional capacity.15 Of additional interest, Maryanovich et al. have recently described how the aging HSC niche is associated with a distinct loss of functional SNS nerve fibers, postulating that denervation-associated remodeling would lead to ‘aged’ HSC.16
Méndez-Ferrer et al. extended their original observations and demonstrated that SNS fibers intrinsically involved in support- ing Schwann cells and nestin+ MSC are reduced in the marrow of MPN patients compared to healthy individuals.14 Schwann cell death is initiated following mutant-HSC IL-1β production, and the resultant denervation ultimately leads to a reduction in so-termed ‘beneficial MSC’ and facilitates expansion of clonal mutant-HSC within the niche. During disease progression, the supportive microenviroment is further disrupted by mutant- HSC-mediated hypercytokinemia and thus the MSC popula- tion and the osteoblast lineage cells continue to modulate. In the same publication, an MPN murine model was used to demonstrate that restoration of sympathetic regulation of Nestin+ MSC induced via β3-agonist exposure abrogated MPN progression and led to a reduction in disease-associated HSC.17 The β3-adrenergic agonist BRL37344 led to reductions in murine BM mutant-HSC-derived progenitors and decreases in neutrophilia, thrombocytosis and marrow fibrosis, associated with a restoration of Nestin+ MSC. In addition, BRL37344 exposure led to a significant decrease in ‘leukemic’ stem cells. This pivotal work rapidly led to conceptualization of adrener- gic nervous system modulation as a novel therapeutic approach in MPN.
In solid tumor oncogenesis, in vitro studies investigating neuro-biological regulation of tumor establishment, aggres- siveness and metastases have emerged over the last five years.18-20 By way of example, in contrast to what has been described above in MPN, Magnon et al. studied mice bearing PC-3 prostate tumor xenografts and human prostate tumor specimens, and demonstrated that prostate cancer growth was down-regulated following chemical or surgical sympathecto- my or deletion of stromal β3-adrenergic receptors; tumor sam- ples demonstrated higher densities of adrenergic (surrounding the tumor) and cholinergic (invading the tumor) nerve fibers associated with poorer prognosis, and that the cholinergic parasympathetic nerve fibers were associated with cancer dis- semination.20 Further links between neuro-modulation and prostate cancer have been suggested by a Norwegian epidemi- ological study suggesting β-blocker use was associated with reduced prostate cancer mortality.21 Other in vivo work has also investigated the importance of SNS modulation in breast, ovar- ian and melanoma tumorigenesis, amongst others, and how
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