Background: Myeloproliferative neoplasms (MPN) are a group of chronic haematological disorders. At the molecular level of MPN cells, the gain-of-function mutation V617F of the Janus kinase 2 (JAK2) leads to a constitutive activation of the downstream signaling cascade and is a conventional criteria for diagnosis. Here, the functional role of the tumor suppressor SHIP1 (SH2 domain containing inositol-5 phosphatase 1) in the pathogenesis of MPNs was investigated.
Methods: Primary blood samples of MPN-patients were analysed using Western Blot technique regarding the level of SHIP1 expression. Moreover, SHIP1 and SHIP1-mutations were lentivirally transduced in the JAK2-V617F-positive UKE-1 cell line and expression was monitored over time. In addition, we examined SHIP1 reconstitution by inhibition of JAK2-V617F. Furthermore, we transfected SHIP1-expressing cells with a JAK2-V617F respectively a BCR-ABL construct and investigated changes in SHIP1 expression.
Results: Four out of five MPN-patient samples showed a loss or a reduction in SHIP1 expression. We identified JAK2 as a negative regulator of SHIP1 expression in MPN cells and inhibition of JAK2-V617F implicates a reconstituted SHIP1 expression. This is significant because SHIP1 negatively regulates the AKT signaling pathway and in consequence the reconstitution of SHIP1 expression leads to a decreased cell growth. Moreover, we examined the impact of SHIP1 and patient-derived SHIP1-mutations on AKT phosphorylation and show the benefit of a combined therapy in MPN cells with inhibitors of the AKT/mTOR pathway.
Conclusion: In summary, the data suggest that SHIP1 may play a role during the development of MPNs and could be the basis for establishing a targeted therapy.
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http://dx.doi.org/10.1016/j.biocel.2022.106229 | DOI Listing |
Heliyon
January 2025
Wolfson Sensory, Pain and Regeneration Centre, King's College London, London, United Kingdom.
Neuropathic pain following peripheral nerve injury results from maladaptive changes in neurons and immune cells contribution to mechanisms underlying chronic pain. Specifically, in dorsal root ganglia (DRG), sensory neuron cell bodies release extracellular vesicles (EVs) which promote pro-inflammatory macrophage accumulation that facilitates nociceptive signalling. Here, we show that macrophages shuttle EVs to neurons.
View Article and Find Full Text PDFEur J Immunol
December 2024
Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, USA.
IgE-mediated stimulation of monocytes regulates multiple cellular functions including cellular maturation, cytokine release, antiviral responses, and T-cell differentiation. Expression of the high-affinity IgE receptor, FcεRI, is closely linked to serum IgE levels and atopic disease. The signaling molecules regulating FcεRI effector functions have been well studied in mast cells and basophils; however, less is known about the signaling and regulatory mechanisms in monocytes.
View Article and Find Full Text PDFJ Inflamm (Lond)
November 2024
Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei, 10002, Taiwan.
Background: Polymorphonuclear neutrophils (PMN) activation by monosodium urate crystals (MSU) is crucial to acute gouty arthritis and subsequent spontaneous remission within 7-10 days. Activated PMNs release neutrophil extracellular traps (NETs) that entrap MSU crystals, forming NET-MSU aggregates. Whether NET-MSU aggregates contribute to the resolution of acute inflammation remains to be elucidated.
View Article and Find Full Text PDFArch Med Res
November 2024
Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic. Electronic address:
Background: Cell cycle progression and leukemia development are tightly regulated processes in which even a small imbalance in the expression of cell cycle regulatory molecules and microRNAs (miRNAs) can lead to an increased risk of cancer/leukemia development. Here, we focus on the study of a ubiquitous, multifunctional, and oncogenic miRNA-hsa-miR-155-5p (miR-155, MIR155HG), which is overexpressed in malignancies including chronic lymphocytic leukemia (CLL). Nonetheless, the precise mechanism of how miR-155 regulates the cell cycle in leukemic cells remains the subject of extensive research.
View Article and Find Full Text PDFNutr Rev
October 2024
Postgraduate Program in Cardiovascular Sciences, Fluminense Federal University, Niterói, Rio de Janeiro, 24070-090, Brazil.
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