STAT5 is Expressed in CD34+/CD38− Stem Cells and Serves as a Potential Molecular Target in Ph-Negative Myeloproliferative Neoplasms

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.

Targeting STAT3 and STAT5 in Cancer

“…Additional studies have explored the role of STATs in hematological malignancies. Phospho-STAT5 was shown to play a key role in CD34+/CD38− myeloproliferative neoplasms with downregulation by pharmacologic inhibition of JAK and STAT [24]. JAK/STAT mutations were also identified in patients with the rare and aggressive T-cell prolymphocytic leukemia (T-PLL), pointing towards a possible mode of transformation [25].…”

Phenotypic characterization of leukemia-initiating stem cells in chronic myelomonocytic leukemia

“…The molecular basis of the increase in cytokine receptor expression remains unknown. Since CD25 is a STAT5-target gene in LSC 46 , 47 and STAT5 is a well-known driver in AML 48 , 49 , an attractive hypothesis would be that oncogenic signaling through STAT5 promotes expression of CD25 in post-CMML sAML LSC.…”

A case of JAK2V617F-positive essential thrombocythemia where allele burden was reduced by a PD-1 inhibitor

“…Sufficient anti-tumor immunity is latent and anti-tumor immunotherapy is considered an effective treatment strategy for MPN [19,20]. However, PD-L1 expression was induced in the tumor by JAK2V617F mutation [4,5]. In contrast, it has been reported that T cells in peripheral blood highly express PD-1 [21].…”

“…Several recent reports on malignant tumors showed the effectiveness of immune checkpoint inhibitors [2,3]. In MPN, the Janus kinase/signal transducers and activators of transcription signaling pathway is activated via JAK2 mutation at position 617 (JAK2V617), leading to the expression of the immune checkpoint factor programmed death ligand-1 (PD-L1) [4,5].…”