Dysregulation of the bone marrow niche contributes to the pathogenesis of myeloproliferative neoplasms

The bone marrow niche is the local tissue microenvironment that maintains and regulates stem cells for hematopoiesis. It is comprised of many different cell types that work together to create a functional network. Myeloproliferative neoplasms (MPN) result in a disruption of the balance of this network due to inherent increases in proinflammatory cytokines, skewed adaptive and innate immune responses, and ‘cross-talk’ between the normal and mutated hematopoietic stem cells (HSC), all within endosteal and vascular niches and the extracellular matrix. This contributes to disease progression and drug resistance.

The impact of MPN on the bone marrow niche, and how they can be targeted, was recently reviewed by Natalia Curto-Garcia, Donal P McLornan, and MPN Hub Steering Committee member Claire Harrison in a publication in the journal Haematologica. ¹

What is the bone marrow niche and how is it disrupted in MPN?

The bone marrow niche is comprised of the endosteal niche, the vascular niche, the sympathetic nervous system, and the extracellular matrix. MPN are often associated with Janus kinase-2 (JAK2) V617F mutations in HSCs, which promote their proliferation, survival, and migration, therefore giving these cells a clonal advantage to dominate the bone marrow niche compared to non-mutated cells.

The endosteal niche¹

Normal function

• Comprised mainly of osteoblasts, osteoclasts, and spindle-shaped N-cadherin⁺ osteoblasts (SNO cells), which regulate maintenance, proliferation, and differentiation of HSC through expression of granulocyte-colony stimulating factor and interlukin-6, CXCL12, angiopoietin-1, and osteopontin to regulate HSC trafficking.

Abnormal function in MPN

• MPN mutations in the endosteal niche result in a self-reinforcing cycle of clonal cells, which impair normal hematopoiesis.
• Clonal bone marrow mesenchymal stem cells (BMSCs) promote expansion and overproduction of inflammatory cytokines (TPO, CCL3, TNF-β, and Notch) in osteoblasts, which in turn promote fibrosis.

• Osteoblasts have reduced CXCL12 expression, which effects HSC mobilization.
• JAK2-mutated monocytes have enhanced osteoclast formation ability, which favors the survival of clonal MPN HSCs.

The vascular niche¹

Normal function

• Comprised of sinusoidal blood vessels, endothelial cells, stromal elements, fibronectin, and collagen, which regulate the migration of HSCs, hypoxia status, and the production of inflammatory cytokines and chemokines.
• CXCL12-abundant reticular (CAR) cells, a subpopulation of BMSCs, induce quiescence of HSCs.

Abnormal function in MPN

• Alteration of the CXCL12 pathway in stem cells results in an upregulation of JAK2-mutated endothelial cells, which promote the abnormal proliferation and survival of mutated HSC, and at the same time, inhibit normal HSC functionality.
• Mutated HSC also support neo-angiogenesis by producing vascular endothelial growth factor (VEGF).
• Overproduction of inflammatory markers induces fibrosis.
• Changes in hypoxia-induced signaling results in quiescence of HSCs.

The sympathetic nervous system¹

Normal function

• Changing adrenergic signals mediate temporary downregulation of CXCL12 leading to circadian fluctuations of circulating HSC.

Abnormal function in MPN

• A local neuropathy can occur in MPN bone marrow due to permanent reduction of Nestin⁺ and CXCL12 expression on BMSC, thereby reducing the pool of quiescent HSC and promoting JAK2⁺ HSC expansion.

The extracellular matrix (ECM) ¹

Normal function

• The non-cellular space that consists of up to 300 protein components, enzymes, and growth factors (e.g., TGFβ1, PDGF, and VEGF), which drive the maintenance of HSCs.

Abnormal function in MPN

• Increased production of inflammatory cytokines and growth factors (TGFβ-1, PDGF, VEGF) which promote fibrogenesis and production of collagen.
• Increased levels of VEGF promote the maturation and migration of megakaryocytes.
• Decreased production of matrix metalloproteinases and an increase of lysyl oxidase promote fibrosis and collagen accumulation.

Therapeutics that effect the bone marrow niche¹

Currently, allogeneic stem cell transplantation is the only curative treatment for myelofibrosis (MF). However, many patients are ineligible because of age, co-morbidities, lack of a suitable donor, or risk profile. Therefore, treatment with therapeutics is the next best option, with ruxolitinib, a JAK1/2 inhibitor, being the only licensed agent for the treatment of myelofibrosis. Its approval was based on the COMFORT-I and -II trials, which showed an improvement in overall survival. Other agents that have been tested in clinical trials include inhibitors of histone deacetylases, telomerase, and MDM2, which have been summarized in Table 1.

Table 1. Selection of therapeutics that have been tested in clinical trials in patients with PMF ¹

ET, essential thrombocythemia; HDACi, histone deacetylase inhibitor; IWG-MRT, International Working Group-Myeloproliferative Neoplasms Research and Treatment; JAKi, Janus kinase inhibitor; MF, myelofibrosis; ORR, overall response rate; OS, overall survival; PV polycythemia vera.
Inhibitor	Drug	Trial	Result
JAKi	Pacritinib	PERSIST-I and -II (see more here)	In patients with MF with thrombocytopenia, 18% had a splenic volume reduction ≥ 35%.
	Momelotinib	SIMPLIFY 1 (vs ruxolitinib) (see more here)	At Week 24, 66.5.% of patients with MF were transfusion independent 26.5% of patients had a splenic volume reduction ≥ 35%.
		SIMPLIFY 2 (vs BAT)	7% of patients had a splenic volume reduction ≥ 35%.
	Fedratinib	JAKARTA-1 (see more here)	In patients with MF who were ruxolitinib resistant/intolerant, 36% and 40% of patients had a splenic volume reduction ≥ 35% (400 mg and 500 mg dose group, respectively).
		JAKARTA-2	55% of patients had a splenic volume reduction ≥ 35%.
HDACi	Panobinostat	NCT01298934	In combination with ruxolitinib in patients with MF; the ORR was 36% by IWG-MRT. Median splenic volume reduction was 34%. JAK2 allele burden decreased to 6.8%.
Telomerase inhibitor	Imetelstat	NCT02426086	In patients with MF, OS was 19.9 months and 29.9 months for low dose and high dose, respectively. However, 93% of patients discontinued treatment, of which 25% were due to adverse events.
		NCT01243073	In patients with ET, 89% achieved complete hematological response. 7/8 patients achieved molecular response with an allele burden reduction between 15–66%. 67% of patients had a reduction of at least one grade of bone marrow fibrosis.
MDM2i	Idasanutlin	NCT02407080 (see more here)	In patients with PV or ET, there was a 58% response with monotherapy and 50% response with combined therapy after six cycles.

Therapeutics targeting bone marrow fibrosis have been unsuccessful so far¹

A number of therapeutics that target bone marrow fibrosis in MPN have been tested recently but have proven unsuccessful in clinical trials. IPI926, an oral hedgehog inhibitor, was studied as a monotherapy, with no significant improvements in fibrosis. Sonidegib (LDE225), a SMO receptor antagonist, tested in a phase Ib/II study in combination with ruxolitinib, only demonstrated spleen and symptom responses in a minority of patients. In vivo studies with the anti-fibrotic agent, pirfenidone, also showed minimal clinical benefits, and fresolimumab, a monoclonal antibody against TGF-β, demonstrated no relevant changes in MF.

Conclusion

The balance of the bone marrow niche is disrupted by MPN-mutated HSC, which promote a self-reinforcing environment that enhances their proliferation over normal hematopoiesis and fosters the development of myelofibrosis. These changes may eventually lead to therapeutic resistance and drive disease progression towards the blastic phase of the disease. Therapeutics against various components of the bone marrow niche have been trialed and have led to variable results. As the bone marrow niche is highly complex, it is likely that combinatorial or sequenced therapeutic strategies will be required to better treat this disease.