Proinflammatory Cytokine IL-6 and JAK-STAT Signaling Pathway in Myeloproliferative Neoplasms.
The recent JAK1/2 inhibitor trial in myeloproliferative neoplasms (MPNs) showed that reducing inflammation can be more beneficial than targeting gene mutants. We evaluated the proinflammatory IL-6 cytokine and JAK-STAT signaling pathway related genes in circulating CD34(+) cells of MPNs. Regarding laboratory data, leukocytosis has been observed in polycythemia vera (PV) and JAK2V617F mutation positive versus negative primary myelofibrosis (PMF) patients. Moreover, thrombocytosis was reduced by JAK2V617F allele burden in essential thrombocythemia (ET) and PMF. 261 significantly changed genes have been detected in PV, 82 in ET, and 94 genes in PMF. The following JAK-STAT signaling pathway related genes had augmented expression in CD34(+) cells of MPNs: CCND3 and IL23A regardless of JAK2V617F allele burden; CSF3R, IL6ST, and STAT1/2 in ET and PV with JAK2V617F mutation; and AKT2, IFNGR2, PIM1, PTPN11, and STAT3 only in PV. STAT5A gene expression was generally reduced in MPNs. IL-6 cytokine levels were increased in plasma, as well as IL-6 protein levels in bone marrow stroma of MPNs, dependent on JAK2V617F mutation presence in ET and PMF patients. Therefore, the JAK2V617F mutant allele burden participated in inflammation biomarkers induction and related signaling pathways activation in MPNs.
Institute for Medical Research, University of Belgrade, 11129 Belgrade, Serbia.
Vladan P
VP
Čokić
Institute for Medical Research, University of Belgrade, 11129 Belgrade, Serbia.
Olivera
O
Mitrović-Ajtić
Clinic of Endocrinology, Diabetes and Diseases of Metabolism, Clinical Center of Serbia, 11000 Belgrade, Serbia.
Bojana B
BB
Beleslin-Čokić
Institute for Medical Research, University of Belgrade, 11129 Belgrade, Serbia.
Dragana
D
Marković
Institute for Medical Research, University of Belgrade, 11129 Belgrade, Serbia.
Marijana
M
Buač
Institute for Medical Research, University of Belgrade, 11129 Belgrade, Serbia.
Miloš
M
Diklić
Clinic of Hematology, Clinical Center of Serbia, 11000 Belgrade, Serbia.
Nada
N
Kraguljac-Kurtović
Clinic of Endocrinology, Diabetes and Diseases of Metabolism, Clinical Center of Serbia, 11000 Belgrade, Serbia ; Medical Faculty, University of Belgrade, 11000 Belgrade, Serbia.
Svetozar
S
Damjanović
Institute for Medical Research, University of Belgrade, 11129 Belgrade, Serbia.
Pavle
P
Milenković
Clinic of Hematology, Clinical Center of Serbia, 11000 Belgrade, Serbia ; Medical Faculty, University of Belgrade, 11000 Belgrade, Serbia.
Mirjana
M
Gotić
Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
Puri K
PK
Raj
D000483:Alleles; D018952:Antigens, CD34 / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D015850:Interleukin-6 / Q000097:blood*; D053613:Janus Kinase 1 / Q000097:blood*; D007964:Leukocytosis / Q000150:complications; D008297:Male; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000097:blood / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D011087:Polycythemia Vera / Q000097:blood / Q000276:immunology; D055728:Primary Myelofibrosis / Q000097:blood / Q000276:immunology; D050791:STAT Transcription Factors / Q000097:blood*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D013920:Thrombocythemia, Essential / Q000097:blood / Q000276:immunology; D013922:Thrombocytosis / Q000097:blood / Q000276:immunology
D018952:Antigens, CD34; D015415:Biomarkers; C508600:IL6 protein, human; D015850:Interleukin-6; D050791:STAT Transcription Factors; C507904:JAK1 protein, human; D053613:Janus Kinase 1