Cytokine profiles in polycythemia vera and essential thrombocythemia patients: Clinical implications

Pourcelot, Emmanuel; Trocmé, Candice; Mondet, Julie; Bailly, Sébastien; Toussaint, Bertrand; Mossuz, Pascal

doi:10.1016/j.exphem.2014.01.006

Cited by 112 publications

(121 citation statements)

References 28 publications

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“…Across the various cytokines measured in the plasma of MPN patients, eight chief cytokines have been described; MIP-1β, TNF-α, IL-6, GM-CSF, IFN-γ, G-CSF, IFN-α, and Rantes [24, 25, 34]. The observed concentration of these cytokines in MPN patients is higher than that in normal donors, consistent with other published reports [23].…”

Section: Discussionsupporting

confidence: 83%

Identification of myeloproliferative neoplasm drug agents via predictive simulation modeling: assessing responsiveness with micro-environment derived cytokines

Kobayashi

Vali²,

Kumar

et al. 2016

Oncotarget

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Previous studies have shown that the bone marrow micro-environment supports the myeloproliferative neoplasms (MPN) phenotype including via the production of cytokines that can induce resistance to frontline MPN therapies. However, the mechanisms by which this occurs are poorly understood. Moreover, the ability to rapidly identify drug agents that can act as adjuvants to existing MPN frontline therapies is virtually non-existent. Here, using a novel predictive simulation approach, we sought to determine the effect of various drug agents on MPN cell lines, both with and without the micro-environment derived inflammatory cytokines. We first created individual simulation models for two representative MPN cell lines; HEL and SET-2, based on their genomic mutation and copy number variation (CNV) data. Running computational simulations on these virtual cell line models, we identified a synergistic effect of two drug agents on cell proliferation and viability; namely, the Jak2 kinase inhibitor, G6, and the Bcl-2 inhibitor, ABT737. IL-6 did not show any impact on the cells due to the predicted lack of IL-6 signaling within these cells. Interestingly, TNFα increased the sensitivity of the single drug agents and their use in combination while IFNγ decreased the sensitivity. In summary, this study predictively identified two drug agents that reduce MPN cell viability via independent mechanisms that was prospectively validated. Moreover, their efficacy is either potentiated or inhibited, by some of the micro-environment derived cytokines. Lastly, this study has validated the use of this simulation based technology to prospectively determine such responses.

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Section: Discussionsupporting

confidence: 83%

Identification of myeloproliferative neoplasm drug agents via predictive simulation modeling: assessing responsiveness with micro-environment derived cytokines

Kobayashi

Vali²,

Kumar

et al. 2016

Oncotarget

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“…3 These cytokines affect marrow mesenchymal cells that are not involved by the malignant process. [3][4][5][6][7][8][9] Recently, neutrophil gelatinase-associated lipocalin (lipocalin-2; LCN2) has been implicated in the pathobiology of myeloproliferative neoplasms (MPNs). [10][11][12][13] LCN2 promotes the proliferation of the malignant clone in chronic myeloid leukemia.…”

Section: Introductionmentioning

confidence: 99%

Lipocalin produced by myelofibrosis cells affects the fate of both hematopoietic and marrow microenvironmental cells

Lü

Xia

Liu

et al. 2015

Blood

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Key Points• LCN2 acts to generate reactive oxygen species, leading to increased DNA strand breaks and apoptosis in normal CD34 1 cells.• LCN2 promotes the generation of osteoblasts but diminishes adipogenesis, resembling the composition of the MF marrow microenvironment.Myelofibrosis (MF) is characterized by cytopenias, constitutional symptoms, splenomegaly, and marrow histopathological abnormalities (fibrosis, increased microvessel density, and osteosclerosis). The microenvironmental abnormalities are likely a consequence of the elaboration of a variety of inflammatory cytokines generated by malignant megakaryocytes and monocytes. We observed that levels of a specific inflammatory cytokine, lipocalin-2 (LCN2), were elevated in the plasmas of patients with myeloproliferative neoplasms (MF > polycythemia vera or essential thrombocythemia) and that LCN2 was elaborated by MF myeloid cells. LCN2 generates increased reactive oxygen species, leading to increased DNA strand breaks and apoptosis of normal, but not MF, CD34 1 cells. Furthermore, incubation of marrow adherent cells or mesenchymal stem cells with LCN2 increased the generation of osteoblasts and fibroblasts, but not adipocytes. LCN2 priming of mesenchymal stem cells resulted in the upregulation of RUNX2 gene as well as other genes that are capable of further affecting osteoblastogenesis, angiogenesis, and the deposition of matrix proteins. These data indicate that LCN2 is an additional MF inflammatory cytokine that likely contributes to the creation of a cascade of events that results in not only a predominance of the MF clone but also a dysfunctional microenvironment. (Blood. 2015;126(8):972-982)

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“…The biomolecular underpinnings of PV‐related symptoms have not been fully elucidated. However, elevated serum inflammatory cytokine levels have been reported in MPN patients (Barbui et al , 2011; Vaidya et al , 2012; Pourcelot et al , 2014) and may contribute to the severity of symptoms, including itching and night sweats (Tefferi et al , 2011; Squires et al , 2013). Other common aspects of the PV disease state, including blood hyperviscosity (Barbui et al , 2013) and splenomegaly (Mesa et al , 2007), may also play a role in the symptom profile of some patients.…”

mentioning

confidence: 99%

The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double‐blind, double‐dummy, symptom study (RELIEF)

et al. 2016

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SummaryThe randomized, double‐blind, double‐dummy, phase 3b RELIEF trial evaluated polycythaemia vera (PV)‐related symptoms in patients who were well controlled with a stable dose of hydroxycarbamide (also termed hydroxyurea) but reported PV‐related symptoms. Patients were randomized 1:1 to ruxolitinib 10 mg BID (n = 54) or hydroxycarbamide (prerandomization dose/schedule; n = 56); crossover to ruxolitinib was permitted after Week 16. The primary endpoint, ≥50% improvement from baseline in myeloproliferative neoplasm ‐symptom assessment form total symptom score cytokine symptom cluster (TSS‐C; sum of tiredness, itching, muscle aches, night sweats, and sweats while awake) at Week 16, was achieved by 43·4% vs. 29·6% of ruxolitinib‐ and hydroxycarbamide‐treated patients, respectively (odds ratio, 1·82; 95% confidence interval, 0·82–4·04; P = 0·139). The primary endpoint was achieved by 34% of a subgroup who maintained their hydroxycarbamide dose from baseline to Weeks 13–16. In a post hoc analysis, the primary endpoint was achieved by more patients with stable screening‐to‐baseline TSS‐C scores (ratio ≤ 2) receiving ruxolitinib than hydroxycarbamide (47·4% vs. 25·0%; P = 0·0346). Ruxolitinib treatment after unblinding was associated with continued symptom score improvements. Adverse events were primarily grades 1/2 with no unexpected safety signals. Ruxolitinib was associated with a nonsignificant trend towards improved PV‐related symptoms versus hydroxycarbamide, although an unexpectedly large proportion of patients who maintained their hydroxycarbamide dose reported symptom improvement.

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Cytokine profiles in polycythemia vera and essential thrombocythemia patients: Clinical implications

Cited by 112 publications

References 28 publications

Identification of myeloproliferative neoplasm drug agents via predictive simulation modeling: assessing responsiveness with micro-environment derived cytokines

Identification of myeloproliferative neoplasm drug agents via predictive simulation modeling: assessing responsiveness with micro-environment derived cytokines

Lipocalin produced by myelofibrosis cells affects the fate of both hematopoietic and marrow microenvironmental cells

The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double‐blind, double‐dummy, symptom study (RELIEF)

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