Abstract
BackgroundHTLV-1 is a retrovirus that infects over 20 million people worldwide and is responsible for the hematopoietic malignancy adult T cell leukemia (ATL). We previously demonstrated that Notch is constitutively activated in ATL cells. Activating genetic mutations were found in Notch; however, Notch signaling was also activated in the absence of genetic mutations suggesting the existence of other mechanisms.MethodsWe analyzed the expression of Notch receptor ligands in HTLV-I-transformed cells, ATL patient-derived cell lines, and fresh uncultured ATL samples by RT-PCR, FACS, and immunohistochemistry. We then investigated viral and cellular molecular mechanisms regulating expression of JAG1. Finally, using shRNA knock-down and neutralizing antibodies, we investigated the function of JAG1 in ATL cells.ResultsHere, we report the overexpression of the Notch ligand, JAG1, in freshly uncultured ATL patient samples compared to normal PBMCs. We found that in ATL cells, JAG1 overexpression relies upon the viral protein Tax and cellular miR-124a, STAT3, and NFATc1. Interestingly, our data show that blockade of JAG1 signaling dampens Notch1 downstream signaling and limits cell migration of transformed ATL cells.ConclusionsOur results suggest that targeting JAG1 can block Notch1 activation in HTLV-I-transformed cells and represents a new target for immunotherapy in ATL patients.
Highlights
HTLV-1 is a retrovirus that infects over 20 million people worldwide and is responsible for the hematopoietic malignancy adult T cell leukemia (ATL)
Our results suggest that targeting JAG1 can block Notch1 activation in HTLV-I-transformed cells and represents a new target for immunotherapy in ATL patients
Overexpression of JAG1 in HTLV-I-transformed and ATL-derived patient cell lines We used RT-PCR to test the expression of Notch receptor ligands JAG1, JAG2, delta-like ligand 1 (DLL1), and delta-like ligand 4 (DLL4) in HTLV-I-infected immortalized (IL-2-dependent) and transformed (IL-2-independent) cell lines compared to the HTLV-I-uninfected T cell line, Jurkat, and peripheral blood mononuclear cells (PBMCs) isolated from healthy donors
Summary
HTLV-1 is a retrovirus that infects over 20 million people worldwide and is responsible for the hematopoietic malignancy adult T cell leukemia (ATL). The Notch pathway is one of the most frequently activated signaling pathways in human malignancies. Activating mutations or amplification of the Notch pathway is commonly reported in various types of human cancer. Termination of Notch signaling can occur at, or downstream of, the Notch receptor through ubiquitin ligases Itch/AIP4 (itchy E3 ubiquitin protein ligase) or Nedd (neural precursor cell-expressed developmentally downregulated protein 4) [6, 7]. NICD can be phosphorylated by glycogen synthase kinase 3 beta (GSK3β), which regulates its interaction with the E3 ubiquitin ligase, FBXW7 (F-box and WD repeat domain containing 7). This promotes ubiquitination and proteasome-mediated degradation of NICD [8]
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