Anti-inflammatory cytokines hepatocyte growth factor and interleukin-11 are over-expressed in Polycythemia vera and contribute to the growth of clonal erythroblasts independently of JAK2V617F

Abstract

The V617F activating mutation of janus kinase 2 (JAK2), a kinase essential for cytokine signalling, characterizes Polycythemia vera (PV), one of the myeloproliferative neoplasms (MPN). However, not all MPNs carry mutations of JAK2, and in JAK2-mutated patients, expression of JAK2V617F does not always result in clone expansion. In the present study, we provide evidence that inflammation-linked cytokines are required for the growth of JAK2V617F-mutated erythroid progenitors. In a first series of experiments, we searched for cytokines overexpressed in PV using cytokine antibody (Ab) arrays, and enzyme-linked immunosorbent assays for analyses of serum and bone marrow (BM) plasma, and quantitative reverse transcription-PCRs for analyses of cells purified from PV patients and controls. We found that PV patients over-expressed anti-inflammatory hepatocyte growth factor (HGF) and interleukin-11 (IL-11), BM mesenchymal stromal cells (BMMSCs) and erythroblasts being the main producers. In a second series of experiments, autocrine/paracrine cytokine stimulation of erythroblasts was blocked using neutralizing Abs specific for IL-11 or c-MET, the HGF receptor. The growth of JAK2V617F-mutated HEL cells and PV erythroblasts was inhibited, indicating that JAK2-mutated cells depend on HGF and IL-11 for their growth. Additional experiments showed that transient expression of JAK2V617F in BaF-3/erythropoietin receptor cells, and invalidation of JAK2V617F in HEL cells using anti-JAK2 small interfering RNA, did not affect HGF and IL-11 expression. Thus, anti-inflammatory HGF and IL-11 are upregulated in PV and their overproduction is not a consequence of JAK2V617F. As both cytokines contribute to the proliferation of PV erythroblasts, blocking the c-MET/ HGF/IL-11 pathways could be of interest as an additional therapeutic option in PV.

The JAK2 46/1 haplotype: a marker of inappropriate myelomonocytic response to cytokine stimulation, leading to increased risk of inflammation, myeloid neoplasm, and impaired defense against infection?

“…There is proof of yet unexplained JAK2V617F-independent cytokine over-production in MPN, by both bone marrow stromal cells and malignant hematopoietic progenitors. 19,20 The cytokines that were found to be over-produced were all linked to inflammation as well as capable of stimulating myelopoiesis, an unsurprising finding since evidence of inflammation in MPN is abundant. 21 Future studies investigating the possible expression and consequences of INSL6 and INLS4 expression in cell types relevant to myelopoiesis and their relationship to the 46/1 status of patients should bring new and important insights into the pathogenesis of myeloid neoplasms as well as of inflammatory diseases.…”

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

“…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.…”

A novel, somatic, transforming mutation in the extracellular domain of Epidermal Growth Factor Receptor identified in myeloproliferative neoplasm

“…Two separate studies have suggested a functional role for HGF/MET in PV 22, 23 , and a previous exome sequencing study of MPN patient samples identified acquired mutations in MET (V1247A, adjacent to the somatic mutation identified in our screen) and in ERBB2 (L494F) 24 . Overall, mutations in ERBB receptors, MET and ALK are rare in MPN (those described to date are summarized in Suppl.…”