Abstract
In myelofibrosis, pathologically enhanced extracellular matrix production due to aberrant cytokine signalling and clonal megakaryocyte functions result(s) in impaired hemopoiesis. Disease progression is still determined by detecting reticulin and collagen fibrosis with Gomori’s silver impregnation. Here, we tested whether the expression growth related biomarkers L-NGFR/CD271, phospho-ERK1-2 and CXCL12 can be linked to the functional activation of bone marrow stromal cells during primary myelofibrosis progression. Immunoscores for all tested biomarkers showed varying strength of positive statistical correlation with the silver impregnation based myelofibrosis grades. The intimate relationship between spindle shaped stromal cells positive for all three markers and aberrant megakaryocytes was likely to reflect their functional cooperation. L-NGFR reaction was restricted to bone marrow stromal cells and revealed the whole length of their processes. Also, L-NGFR positive cells showed the most intersections, the best statistical correlations with myelofibrosis grades and the strongest interrater agreements. CXCL12 reaction highlighted stromal cell bodies and a weak extracellular staining in line with its constitutive release. Phospho-ERK1-2 reaction showed a similar pattern to CXCL12 in stromal cells with an additional nuclear staining in agreement with its role as a transcription factor. Both p-ERK1-2 and CXCL12 were also expressed at a moderate level in sinus endothelial cells. Connexin 43 gap junction communication channels, known to be required for CXCL12 release to maintain stem cell niche, were also expressed progressively in the myelofibrotic stromal network as a support of compartmental functions. Our results suggest that, diverse growth related pathways are activated in the functionally coupled bone marrow stromal cells during myelofibrosis progression. L-NGFR expression can be a useful biological marker of stromal cell activation which deserves diagnostic consideration for complementing Gomori’s silver impregnation.
Highlights
Primary myelofibrosis (PMF) belongs to a group of Philadelphia chromosome (BCR-ABL1)-negative myeloproliferative neoplasms (MPN) of the multipotent hematopoietic stem cells, including polycythaemia vera (PV) and essential thrombocythemia (ET) [1]
Myelofibrosis is an adverse prognostic factor in MPNs, which is mainly driven by impaired megakaryocyte functions resulting in the elevated expression of inflammatory cytokines, transforming growth factor-β (TGF-β), platelet derived growth factor (PDGF), as well as the aberrant JAK-STAT signaling as a result of JAK2V617F, MPL515 L/K or CALR mutations [3]
In normal-looking, intact areas of myelofibrosis with grade 1 (MF-1) bone marrow samples Low affinity nerve growth factor receptor (L-NGFR) was detected in the bodies and processes of elongated, unevenly arranged stromal cells both in peri-trabecular and peri-sinusoidal regions with sporadic interconnections similar to Gomori’s silver impregnation (Figure 1A,B)
Summary
Primary myelofibrosis (PMF) belongs to a group of Philadelphia chromosome (BCR-ABL1)-negative myeloproliferative neoplasms (MPN) of the multipotent hematopoietic stem cells, including polycythaemia vera (PV) and essential thrombocythemia (ET) [1]. These malignancies are characterised by clonal proliferation of the myeloid lineages accompanied by progressive stromal cell activation, extracellular matrix production and impeded hemopoesis [2]. Myelofibrosis grading is still based on Gomori’s silver staining, which reveals reticular and collagen fibers proportional with disease progression [4]. Correlations between the expression of these makers and myelofibrosis grades were tested to see if they could support reticulin silver impregnation based prognostic decisions on a biological basis
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