Abstract
Simple SummaryInflammation plays a major role in myeloproliferative neoplasms (MPNs) as regulator of malignant cell growth and mediator of clinical symptoms. Yet chronic inflammation may also be an early event that facilitates the development of MPNs. Here we analysed 42 inflammatory cytokines and report that in patients as well as in UT-7 cell lines, interleukin-1β and interferon-induced protein 10 (IP-10) were the main inflammatory molecules found to be induced by JAK2V617F, the most frequent driving mutation in MPNs. All other inflammatory cytokines were not linked to JAK2V617F, which implies that inflammation likely precedes MPN development at least in subsets of MPN patients. Consistently, a possible cause of early, chronic inflammation may be auto-immunity against glucolipids: we report that 20% of MPN patients presented with anti-glucosylsphingoside auto-antibodies. Since existing treatments can reduce glucosylsphingoside, this lysosphingolipid could become a new therapeutic target for subsets of MPN patients, in addition to JAK2V617F and inflammation.Inflammatory cytokines play a major role in myeloproliferative neoplasms (MPNs) as regulators of the MPN clone and as mediators of clinical symptoms and complications. Firstly, we investigated the effect of JAK2V617F on 42 molecules linked to inflammation. For JAK2V617F-mutated patients, the JAK2V617F allele burden (%JAK2V617F) correlated with the levels of IL-1β, IL-1Rα, IP-10 and leptin in polycythemia vera (PV), and with IL-33 in ET; for all other molecules, no correlation was found. Cytokine production was also studied in the human megakaryocytic cell line UT-7. Wild-type UT-7 cells secreted 27/42 cytokines measured. UT-7 clones expressing 50% or 75% JAK2V617F were generated, in which the production of IL-1β, IP-10 and RANTES was increased; other cytokines were not affected. Secondly, we searched for causes of chronic inflammation in MPNs other than driver mutations. Since antigen-driven selection is increasingly implicated in the pathogenesis of blood malignancies, we investigated whether proinflammatory glucosylsphingosine (GlcSph) may play a role in MPNs. We report that 20% (15/75) of MPN patients presented with anti-GlcSph IgGs, distinguished by elevated levels of 11 cytokines. In summary, only IL-1β and IP-10 were linked to JAK2V617F both in patients and in UT-7 cells; other inflammation-linked cytokines in excess in MPNs were not. For subsets of MPN patients, a possible cause of inflammation may be auto-immunity against glucolipids.
Highlights
An active JAK2/STAT5 pathway is required for an appropriate production of mature myeloid cells.Strong and prolonged activation of the JAK2/STAT5 pathway by erythropoietin (EPO), thrombopoietin (TPO), granulocyte-colony stimulating factor (G-CSF) or certain interleukins, physiologically enhances myelopoiesis, for instance after severe bleeding or during acute or chronic inflammation
Serum samples collected from 75 patients at the time of diagnosis of myeloproliferative neoplasms (MPNs) (27 polycythemia vera (PV), 39 essential thrombocythemia (ET), 9 primary myelofibrosis (PMF)) and 54 healthy donors (HDs) were aliquoted, kept frozen at −80 ◦ C
We and others previously showed that the %JAK2V617F in mRNA and genomic DNA (gDNA) are well correlated [44]
Summary
An active JAK2/STAT5 pathway is required for an appropriate production of mature myeloid cells. Patients may present with clinical symptoms and complications that include fatigue, fever, night sweats, loss of weight, itching, arterial and venous thrombosis, bone marrow fibrosis and splenomegaly; evolution toward acute myeloid leukemia (AML) is rare [13]. IFN-α and JAK inhibitors were reported to act in synergy in MPNs [26,27,28] Both chronic inflammation and the JAK2/CALR/MPL mutants play major roles in the pathogenesis of MPNs, and inflammation cytokines act as stimulants of the mutated clone as well as mediators of clinical symptoms and complications [12,29]. Our second aim was to search for causes of chronic inflammation in MPNs other than mutation(s), and we investigated whether GlcSph stimulation played a role in MPNs
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