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Cell Biol Int. 2019 Feb;43(2):192-206. doi: 10.1002/cbin.11084. Epub 2019 Jan 7.

IL-6 stimulation of DNA replication is JAK1/2 mediated in cross-talk with hyperactivated ERK1/2 signaling.

Author information

1
Department of Molecular Oncology, Institute for Medical Research, University of Belgrade, Belgrade, Serbia.
2
Clinic for Endocrinology, Diabetes and Metabolic Diseases, Genetic Laboratory, Clinical Center of Serbia, Belgrade, Serbia.
3
Clinic of Hematology, Clinical Center of Serbia, Belgrade, Serbia.
4
School of Medicine, University of Belgrade, Belgrade, Serbia.
5
Centro Integrativo de Biología y Química Aplicada (CIBQA), Universidad Bernardo O'Higgins, General Gana 1780, Santiago, 8370854, Chile.
6
Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Abstract

Myeloproliferative neoplasms (MPNs) are developing resistance to therapy by JAK1/2 inhibitor ruxolitinib. To explore the mechanism of ruxolitinib's limited effect, we examined the JAK1/2 mediated induction of proliferation related ERK1/2 and AKT signaling by proinflammatory interleukin-6 (IL-6) in MPN granulocytes and JAK2V617F mutated human erythroleukemia (HEL) cells. We found that JAK1/2 or JAK2 inhibition prevented the IL-6 activation of STAT3 and AKT pathways in polycythemia vera and HEL cells. Further, we showed that these inhibitors also blocked the IL-6 activation of the AKT pathway in primary myelofibrosis (PMF). Only JAK1/2 inhibitor ruxolitinib largely activated ERK1/2 signaling in essential thrombocythemia and PMF (up to 4.6 fold), with a more prominent activation in JAK2V617F positive granulocytes. Regarding a cell cycle, we found that IL-6 reduction of HEL cells percentage in G2M phase was reversed by ruxolitinib (2.6 fold). Moreover, ruxolitinib potentiated apoptosis of PMF granulocytes (1.6 fold). Regarding DNA replication, we found that ruxolitinib prevented the IL-6 augmentation of MPN granulocytes frequency in the S phase of the cell cycle (up to 2.9 fold). The inflammatory stimulation induces a cross-talk between the proliferation linked pathways, where JAK1/2 inhibition is compensated by the activation of the ERK1/2 pathway during IL-6 stimulation of DNA replication.

KEYWORDS:

ERK1/2 signaling; JAK1/2 inhibition; cell cycle; inflammation; myeloproliferative neoplasm

PMID:
30571852
PMCID:
PMC6347554
[Available on 2020-02-01]
DOI:
10.1002/cbin.11084
[Indexed for MEDLINE]

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