Page 33 - Haematologica May 2020

BM niche dysregulation in MPN
with resultant collagen accumulation in MF.64 Tadmor et al. demonstrated that, in MF, all LOX members genes are activated compared to the pattern seen in either ET or PV; postulating that this occurred during fibrogenesis. Of interest, LOXL1 was only expressed in MF, suggesting a relationship with advanced fibrosis.67
In summary, it is evident that the bone marrow niche is profoundly dysregulated on multiple, yet interacting lev- els, in MPN (Table 1). Mutated-MPN-HSC activate a cas- cade of dysregulated signaling and abnormalities in multi- ple key players across the niches, compromising function- ality of both the osteoblastic and vascular niches and ECM. Consequently, these irregularities promote the abnormal proliferation inherent to these disease states. Although our knowledge of the MPN-associated dysregu- lated niche has increased in recent years, further studies are required to help understand how this niche can be suc- cessfully targeted in therapy.
Direct or indirect targeting of the bone marrow
niche in myeloproliferative neoplasms: is there
a role?
To date, the only curative treatment for MF remains allogeneic stem cell transplantation, although this is not a feasible option for many due to age, risk profile, co-mor- bidities, or lack of a suitable donor.68 Many clinicians have familiarity with the JAK1/JAK2 inhibitor (JAKi) ruxolitinib (Novartis, Switzerland), currently the only licensed agent
Table 1. Bone marrow niche in health and myeloproliferative neoplasm. Bone marrow niche in health
in MF; which has demonstrated improvement in disease- related symptomatology, induced reductions in spleen size, and prolonged the overall survival (OS) in many MF patients.69,70 Of note, ruxolitinib has also been used in both PV and ET, particularly in the setting of hydroxycar- bamide resistance or intolerance.71-74 Many other agents have entered the clinical trial arena to address the multiple unmet needs, particularly when individuals are failing or become intolerant of standard therapies, including novel JAKi, BET-inhibitors, BCL-2 inhibitors, HDAC inhibitors, telomerase inhibitors, and MDM2 inhibitors.75-81 Regarding novel JAKi, pacritinib (which is also a FLT3 inhibitor) has been investigated in MF patients with thrombocytopenia showing improvements in splenic responses within both the PERSIST-I and -II studies.82,83 The drug was on clinical hold from 2016 due to concerns regarding cardiac toxicity, but following the Food and Drug Administration (FDA) review and removal of the clinical hold, the PAC203 study has now fully recruited and further studies are planned. Momelotinib, a JAK1/2 inhibitor, demonstrated anemia and transfusion responses in both the SIMPLIFY-1 and 2 clinical trials but it failed to meet the pre-defined clinical end points, although some patients demonstrated symptom, spleen and anemia responses.84,85 This agent will be compared on a random- ized basis to danazol in the upcoming MOMEMTUM study. Fedratinib (Inrebic®, Celgene, USA) is a more selec- tive JAKi than ruxolitinib; both JAKARTA-1 and 2 trials showed this agent to have significant efficacy in MF
Bone marrow niche in MPN
Self-reinforcing of clonal cells. - Osteoblasts:
- Abnormal OB expansion due to overstimulation by BMSC. - Overproduction of inflammatory cytokines.
- Promotion of fibrogenesis.
- Reduction in CXCL12 expression. - Osteoclasts:
- Abnormal stimulation by JAK2 positive monocytes.
- Favoring survival of clonal HSC. - SNO:
- No clear role described yet.
• Alteration CXCL12 pathway: upregulated in JAk2+ endothelial cells, downregulated BMSC- promotes expansion mutated HSC.
• Clonal endothelial cells support neo-angiogenesis by VEGF production.
Endosteal niche: Osteoblasts, Osteoclasts and spindle-shaped N-cadherin+ osteoblast cells
Vascular niche: sinusoidal blood vessels, endothelial cells, stromal elements, fibronectin and collagen
Sympathetic nervous system
Extracellular matrix
• Maintenance, proliferation and differentiation of HSC. • Osteoblasts:
- Interact with CD34+HSC by expressing GSCF and IL6. - Regulate HSC trafficking by expression CXCL12,
angiopoietin-1 and osteopontin. • Osteoclasts:
- Regulatory role.
- Bone resorption.
- Promote HSC mobilization.
• SNO cells:
- Cell-cell contact with HSC.
• Regulate HSC migration .
• Expression of e-selectin by endothelial cells.
• Production of inflammatory chemokines and cytokines.
• Regulation of hypoxia status .
• BMSC-CAR cells express CXCL12- maintenance and
quiescence HSC.
• Macrophage- modulate CXCL12 pathway. • Monocytes- regulate osteoblasts, promote
pro-inflammatory cytokine environment.
• Noradrenaline secretion regulate HSC circulation and functionality .
• Integrity, proliferation and elasticity of BMN.
• Presence of growth factors (TGFβ-1, PEGF, VEGF)
to maintain HSC.
• Increase survival mutated HSC.
• Alteration of HIF-1α and hypoxia status.
• BMSC promote expansion of osteoblasts by cell contact and
excessive TGFβ1, Notch and cytokines.
• Overproduction of inflammatory markers produce
fibrosis.
• Local neuropathy by reduced expression of Nestin+ and CXCL12 promoting HSC expansion.
• Increase cytokines and growth factor levels (TGFβ-1, PEGF, VEGF) promotes fibrogenesis.
• VEGF contributes to MK maturation and migration.
• Decrease of MMP and increase of LOX favoring fibrosis.
SNO: spindle-shaped N-cadherin+ osteoblasts; HSC: hematopoietic stem cells; BMSC: bone marrow mesenchymal cells; VEGF: vascular endothelial growth factor; PDG: platelet-derived growth factor; TGFβ1: transforming growth factor beta; HIF-1α: Hypoxia inducible factor 1-alpha; MK: megakaryocytes; MMP: matrix metalloproteinases; LOX: Lysyl Oxidase.
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