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- Title
STAT5 is Expressed in CD34+/CD38− Stem Cells and Serves as a Potential Molecular Target in Ph-Negative Myeloproliferative Neoplasms.
- Authors
Hadzijusufovic, Emir; Keller, Alexandra; Berger, Daniela; Greiner, Georg; Wingelhofer, Bettina; Witzeneder, Nadine; Ivanov, Daniel; Pecnard, Emmanuel; Nivarthi, Harini; Schur, Florian K. M.; Filik, Yüksel; Kornauth, Christoph; Neubauer, Heidi A.; Müllauer, Leonhard; Tin, Gary; Park, Jisung; de Araujo, Elvin D.; Gunning, Patrick T.; Hoermann, Gregor; Gouilleux, Fabrice
- Abstract
Janus kinase 2 (JAK2) and signal transducer and activator of transcription-5 (STAT5) play a key role in the pathogenesis of myeloproliferative neoplasms (MPN). In most patients, JAK2 V617F or CALR mutations are found and lead to activation of various downstream signaling cascades and molecules, including STAT5. We examined the presence and distribution of phosphorylated (p) STAT5 in neoplastic cells in patients with MPN, including polycythemia vera (PV, n = 10), essential thrombocythemia (ET, n = 15) and primary myelofibrosis (PMF, n = 9), and in the JAK2 V617F-positive cell lines HEL and SET-2. As assessed by immunohistochemistry, MPN cells displayed pSTAT5 in all patients examined. Phosphorylated STAT5 was also detected in putative CD34+/CD38− MPN stem cells (MPN-SC) by flow cytometry. Immunostaining experiments and Western blotting demonstrated pSTAT5 expression in both the cytoplasmic and nuclear compartment of MPN cells. Confirming previous studies, we also found that JAK2-targeting drugs counteract the expression of pSTAT5 and growth in HEL and SET-2 cells. Growth-inhibition of MPN cells was also induced by the STAT5-targeting drugs piceatannol, pimozide, AC-3-019 and AC-4-130. Together, we show that CD34+/CD38− MPN-SC express pSTAT5 and that pSTAT5 is expressed in the nuclear and cytoplasmic compartment of MPN cells. Whether direct targeting of pSTAT5 in MPN-SC is efficacious in MPN patients remains unknown.
- Subjects
CELL lines; FLOW cytometry; HETEROCYCLIC compounds; IMMUNOHISTOCHEMISTRY; GENETIC mutation; MYELOFIBROSIS; MYELOPROLIFERATIVE neoplasms; NEUROTRANSMITTER uptake inhibitors; PHOSPHORYLATION; POLYCYTHEMIA vera; STEM cells; THROMBOCYTOSIS; WESTERN immunoblotting; STAT proteins; JANUS kinases; PHARMACODYNAMICS
- Publication
Cancers, 2020, Vol 12, Issue 4, p1021
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers12041021