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.
Highlights
Classical myeloproliferative neoplasms (MPN) are incurable stem cell disorders characterized by the abnormal expansion of myeloid cells in the bone marrow (BM), elevated blood counts, extramedullary myelopoiesis, and a genetic instability with enhanced risk to transform to secondary acute myeloid leukemia [1,2,3,4,5,6]
Megakaryocytes stained clearly positive for phosphorylated STAT5 (pSTAT5), whereas erythroid cells stained negative for pSTAT5
We found that the JAK-2 blockers and the signal transducer and activator of transcription-5 (STAT5) blockers used in this study are capable of inhibiting the proliferation of primary MPN cells (Figure 6A)
Summary
Classical myeloproliferative neoplasms (MPN) are incurable stem cell disorders characterized by the abnormal expansion of myeloid cells in the bone marrow (BM), elevated blood counts, extramedullary myelopoiesis, and a genetic instability with enhanced risk to transform to secondary acute myeloid leukemia (sAML) [1,2,3,4,5,6]. For patients with advanced MPN or sAML, the only curative approach is allogeneic hematopoietic stem cell transplantation [7,8,9]. This therapy can only be offered to a subset of patients. Disease management is based on symptom control and the use of growth-inhibitory drugs, including interferon-alpha, anagrelide, hydroxyurea or ruxolitinib [10,11,12,13,14,15] These drugs have little if any curative potential and in many cases resistance develops during therapy [10,11,12,13,14,15].
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