Anti-Glucosylsphingosine Autoimmunity, JAK2V617F-Dependent Interleukin-1β and JAK2V617F-Independent Cytokines in Myeloproliferative Neoplasms

• Published in: Cancers Vol. 12; no. 9; p. 2446
• Main Authors: Allain-Maillet, Sophie, Bosseboeuf, Adrien, Mennesson, Nicolas, Bostoën, Mégane, Dufeu, Laura, Choi, Eun Ho, Cleyrat, Cédric, Mansier, Olivier, Lippert, Eric, Le Bris, Yannick, Gombert, Jean-Marc, Girodon, François, Pettazzoni, Magali, Bigot-Corbel, Edith, Hermouet, Sylvie
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 28.08.2020; MDPI
• Subjects: Antigens; Autoimmunity; Blood; Bone marrow; Cancer; Cloning; Cytokines; Granulocytes; Growth factors; IL-1β; Inflammation; Interleukin 1 receptors; IP-10 protein; Leptin; Life Sciences; Multiple myeloma; Mutation; Neutrophils; Pathogenesis; Polycythemia; Polycythemia vera; RANTES; Tumor necrosis factor-TNF; Tumors; CALR exon 9 mutants; IP-10; JAK2V617F; leptin; IL-33; UT-7; CRISPR technology; interleukin-1β (IL-1β); IL-1Rα; glucolipids; inflammation; antigenic stimulation; auto-immunity; myeloproliferative neoplasms (MPNs); glucosylsphingosine (GlcSph); cytokines
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers12092446

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.