Signals emanating from the bone marrow microenvironment, including stromal cells, are thought to support the survival and proliferation of the malignant cells in patients with myeloproliferative neoplasms (MPN). To examine this hypothesis we established a co-culture platform (cells co-cultured directly [cell-on-cell] or indirectly [separated by micropore membrane]) designed to interrogate the interplay between JAK2V617F–positive cells and the stromal cells. Treatment with atiprimod, a potent JAK2 inhibitor, caused marked growth inhibition and apoptosis of human (SET2) and mouse (FDCP-EpoR) JAK2V617F–positive cells, and of primary blood or bone marrow mononuclear cells from patients with polycythemia vera, but these effects were attenuated when any of these cell types were co-cultured (cell-on-cell) with human marrow stromal cell lines (HS5, NK.tert, or TM-R1). Co-culture with stromal cells hampered the ability of atiprimod to inhibit the phosphorylation of JAK2 and the downstream signal transducer and activators of transcription (STAT) 3, and STAT5. This protective effect was maintained in non-contact co-culture assays (JAK2V617F–positive cells separated by 0.4 μm micropore membranes from stromal cells), suggesting a paracrine effect. Cytokine profiling of supernatants from non-contact co-culture assays detected distinctly high levels of IL-6, FGF, and CXCL10/IP10. Anti-IL-6, -FGF, or -CXCL10/IP10 neutralizing antibodies ablated the protective effect of stromal cells and restored atiprimod-induced apoptosis of JAK2V617F–positive cells. Thus, our results suggest that humoral factors secreted by stromal cells protect MPN clones from JAK2 inhibitor therapy, underscoring the importance of targeting the marrow niche in MPN for therapeutic purposes.
Assessing albumin, ALC and PNI might improve prognostication in patients with myelofibrosis and could assist in recognition of patients under increased risk of death.
Upper body adipose tissue accumulation has been associated with clustering of metabolic disorders and increased cardiovascular risk. Neck circumference (NC) indicated that subcutaneous adipose tissue (SAT) in that region is an independent pathogenic depot that might account for the additional risk missed by visceral adipose tissue (VAT). Neck adipose tissue (NAT) is not only one more ectopic depot but has several particular features that might modulate its metabolic role. Besides a controversial impact on obstructive apnea syndrome, neck fat encompasses carotid arteries as an important perivascular adipose tissue (PVAT) depot. With dysfunctional changes in obesity, physiologic vascular regulation is lost and inflammatory signals accelerate atherogenesis. Unexpected was the discovery of brown and beige adipocytes in the neck of human adults. When stimulated, brown adipose tissue (BAT) dissipates energy through thermogenesis and it is associated with other favorable metabolic effects. Moreover, the neck is the region where the browning mechanism was disclosed. With this unique plastic nature, NAT revealed multiple ties, challenging dynamics and potential new therapeutic targets that might have significant implications on metabolic outcomes and vascular risk.
Neoplastic megakaryopoiesis is a dominant feature of Philadelphia-chromosome-negative myeloproliferative neoplasms (Ph- MPNs), and elevated mean-platelet-volume (MPV) is a common finding in these diseases. The clinical and prognostic significances of MPV in patients with primary (PMF) and secondary myelofibrosis (SMF) have not been reported. We retrospectively analyzed 87 patients with myelofibrosis (66 with PMF, 21 with SMF) treated at our institution. MPV was recorded in addition to other hematological and clinical parameters. MPV was elevated in both PMF and SMF patients in comparison to controls, whereas there was no statistically significant difference between PMF and SMF. Elevated MPV was associated with lower platelets (P = 0.016), higher white blood cells (P = 0.015), higher percentage of circulatory blasts (P = 0.009), higher lactate dehydrogenase (P = 0.011), larger spleen size (P = 0.014) and higher Dynamic International Prognostic score category (P = 0.027), while there was no statistically significant association with driver mutations or degree of bone marrow fibrosis. Higher MPV was univariately associated with inferior overall survival in the whole cohort (HR = 3.82, P = 0.006), PMF (HR = 4.35, P = 0.007) and SMF patients (HR = 7.22, P = 0.034). These associations remained significant in multivariate analyses adjusted for DIPSS. Higher MPV is associated with more aggressive disease features and exhibits powerful independent prognostic properties in both PMF and SMF settings.
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