AML1-ETO,

The Wilms' tumor gene WT1 is overexpressed in most of human leukemias regardless of disease subtypes. To characterize the expression pattern of WT1 during normal and neoplastic hematopoiesis, we generated a knock-in reporter green fluorescent protein (GFP) mouse (WT1 GFP/ þ ) and assayed for WT1 expression in normal and leukemic hematopoietic cells. In normal hematopoietic cells, WT1 was expressed in none of the long-term (LT) hematopoietic stem cells (HSC) and very few (o1%) of the multipotent progenitor cells. In contrast, in murine leukemias induced by acute myeloid leukemia 1 (AML1)/ ETO þ TEL/PDGFbR or BCR/ABL, WT1 was expressed in 40.5 or 38.9% of immature c-kit þ lin À Sca-1 þ (KLS) cells, which contained a subset, but not all, of transplantable leukemic stem cells (LSCs). WT1 expression was minimal in normal fetal liver HSCs and mobilized HSCs, both of which are stimulated for proliferation. In addition, overexpression of WT1 in HSCs did not result in proliferation or expansion of HSCs and their progeny in vivo. Thus, the mechanism by which expansion of WT1-expressing cells occurs in leukemia remains unclear. Nevertheless, our results demonstrate that the WT1 GFP/ þ mouse is a powerful tool for analyzing WT1-expressing cells, and they highlight the potential of WT1, as a specific therapeutic target that is expressed in LSCs but not in normal HSCs.

Background Epstein-Barr virus (EBV) is an oncogenic human herpesvirus involved in the development of around 10% of gastric cancers. The overexpression of PD-L1 is one of the features of EBV-associated gastric cancer (EBVaGC); however, the function of PD-L1 has not been studied in EBVaGC. Methods We used three EBVaGC cell lines, SNU719 cells, NCC24 cells, and YCCEL1 cells, to evaluate the PD-L1 expression and function in EBVaGC. Jurkat T-lymphocytes expressing PD-1 were co-cultured with NCC24 and YCCEL1 cells and the cell cycles were analyzed. To study the regulatory mechanism for PD-L1 expression, the 3′UTR of PD-L1 was sequenced, and the effect of inhibitors of the IFN-γ signaling pathway was evaluated. Results All of the EBVaGC cell lines expressed PD-L1, and its expression was further enhanced by stimulation with IFNγ. In Jurkat T-cells co-cultured with IFN-γ-stimulated NCC24 and YCCEL1 cells, the number of cells in the G0/G1 phase was significantly increased. This G0/G1 arrest was partially released by administration of anti-PD-L1 antibody. We found SNPs in PD-L1 3′UTR nucleotide sequences that were located at seed regions for microRNAs. Treatment of EBVaGC cell lines with JAK2-inhibitor, PI3K-inhibitor, and mTOR inhibitor reduced the level of PD-L1 expression to the same level as cells without IFN-γ stimulation. Conclusions EBVaGC cells expressing high levels of PD-L1 suppress T-cell proliferation, and the IFN-γ signaling pathway is involved in the expression of PD-L1.

No abstract

We report on a path-independent insertion-loss (PILOSS) 8 × 8 matrix switch based on Si-wire waveguides, which has a record-small footprint of 3.5 × 2.4 mm2. The PILOSS switch consists of 64 thermooptic Mach-Zehnder (MZ) switches and 49 low-crosstalk intersections. Each of the MZ switches and intersections employs directional couplers, which enable the composition of a low loss PILOSS switch. We demonstrate successful switching of digital-coherent 43-Gbps QPSK signal.