Acute myelogenous leukemia (AML) is the most common adult leukemia, characterized by the clonal expansion of immature myeloblasts initiating from rare leukemic stem (LS) cells. To understand the functional properties of human LS cells, we developed a primary human AML xenotransplantation model using newborn nonobese diabetic/severe combined immunodeficient/interleukin (NOD/SCID/IL)2r gamma(null) mice carrying a complete null mutation of the cytokine gamma c upon the SCID background. Using this model, we demonstrated that LS cells exclusively recapitulate AML and retain self-renewal capacity in vivo. They home to and engraft within the osteoblast-rich area of the bone marrow, where AML cells are protected from chemotherapy-induced apoptosis. Quiescence of human LS cells may be a mechanism underlying resistance to cell cycle-dependent cytotoxic therapy. Global transcriptional profiling identified LS cell-specific transcripts that are stable through serial transplantation. These results indicate the potential utility of this AML xenograft model in the development of novel therapeutic strategies targeted at LS cells.

Purpose: We have recently reported EBV+ B-cell lymphoproliferative disorders (LPD) occurring predominantly in elderly patients, which shared features of EBV+ B-cell neoplasms arising in the immunologically deteriorated patients despite no predisposing immunodeficiency and were named as senile or age-related EBV+ B-cell LPDs.To further characterize this disease, age-related EBV+ B-cell LPDs were compared with EBV-negative diffuse large B-cell lymphomas (DLBCL). Experimental Design: Among 1,792 large B-cell LPD cases, 96 EBV+ cases with available clinical data set were enrolled for the present study. For the control group, 107 patients aged over 40 years with EBV-negative DLBCL were selected.We compared clinicopathologic data between two groups and determined prognostic factors by univariate and multivariate analysis. Results: Patients with age-related EBV+ B-cell LPDs showed a higher age distribution and aggressive clinical features or parameters than EBV-negative DLBCLs: 44% with performance status >1, 58% with serum lactate dehydrogenase level higher than normal, 49% with B symptoms, and higher involvement of skin and lung. Overall survival was thus significantly inferior in age-related EBV+ group than in DLBCLs. Univariate and multivariate analyses further identified two factors, B symptoms and age older than 70 years, independently predictive for survival. A prognostic model using these two variables well defined three risk groups: low risk (no adverse factors), intermediate risk (one factor), and high risk (two factors). Conclusions: These findings suggest that age-related EBV+ B-cell LPDs constitute a distinct group, and innovative therapeutic strategies such as EBV-targeted T-cell therapy should be developed for this uncommon disease.

Key Points• PD-L1 expression is associated with poor prognosis in DLBCL.• The double-staining technique is a useful method for identifying and distinguishing PD-L1 1 DLBCL.Programmed cell death ligand 1 (PD-L1) is expressed on both select diffuse large B-cell lymphoma (DLBCL) tumor cells and on tumor-infiltrating nonmalignant cells. The programmed cell death 1 (PD-1)/PD-L1 pathway inhibits host antitumor responses; however, little is known about how this pathway functions in the tumor microenvironment. The aim of this study was to determine the clinicopathological impact of PD-L1 1 DLBCL. (P 5 .0323). This is the first report describing the clinicopathological features and outcomes of PD-L1

EBV-associated T/NK-cell lymphoproliferative disease (T/NK-LPD) is defined as

Human T-cell leukemia virus type 1 (HTLV-1) is the causal agent of a neoplastic disease of CD4+ T cells, adult T-cell leukemia (ATL), and inflammatory diseases including HTLV-1 associated myelopathy/tropical spastic paraparesis, dermatitis, and inflammatory lung diseases. ATL cells, which constitutively express CD25, resemble CD25+CD4+ regulatory T cells (Treg). Approximately 60% of ATL cases indeed harbor leukemic cells that express FoxP3, a key transcription factor for Treg cells. HTLV-1 encodes an antisense transcript, HTLV-1 bZIP factor (HBZ), which is expressed in all ATL cases. In this study, we show that transgenic expression of HBZ in CD4+ T cells induced T-cell lymphomas and systemic inflammation in mice, resembling diseases observed in HTLV-1 infected individuals. In HBZ-transgenic mice, CD4+Foxp3+ Treg cells and effector/memory CD4+ T cells increased in vivo. As a mechanism of increased Treg cells, HBZ expression directly induced Foxp3 gene transcription in T cells. The increased CD4+Foxp3+ Treg cells in HBZ transgenic mice were functionally impaired while their proliferation was enhanced. HBZ could physically interact with Foxp3 and NFAT, thereby impairing the suppressive function of Treg cells. Thus, the expression of HBZ in CD4+ T cells is a key mechanism of HTLV-1-induced neoplastic and inflammatory diseases.