Purpose: Cell adhesion molecule 1 (CADM1), initially identified as a tumor suppressor gene, has recently been reported to be ectopically expressed in primary adult T-cell leukemia–lymphoma (ATL) cells. We incorporated CADM1 into flow-cytometric analysis to reveal oncogenic mechanisms in human T-cell lymphotrophic virus type I (HTLV-I) infection by purifying cells from the intermediate stages of ATL development. Experimental Design: We isolated CADM1- and CD7-expressing peripheral blood mononuclear cells of asymptomatic carriers and ATLs using multicolor flow cytometry. Fluorescence-activated cell sorted (FACS) subpopulations were subjected to clonal expansion and gene expression analysis. Results: HTLV-I–infected cells were efficiently enriched in CADM1+ subpopulations (D, CADM1posCD7dim and N, CADM1posCD7neg). Clonally expanding cells were detected exclusively in these subpopulations in asymptomatic carriers with high proviral load, suggesting that the appearance of D and N could be a surrogate marker of progression from asymptomatic carrier to early ATL. Further disease progression was accompanied by an increase in N with a reciprocal decrease in D, indicating clonal evolution from D to N. The gene expression profiles of D and N in asymptomatic carriers showed similarities to those of indolent ATLs, suggesting that these subpopulations represent premalignant cells. This is further supported by the molecular hallmarks of ATL, that is, drastic downregulation of miR-31 and upregulation of abnormal Helios transcripts. Conclusion: The CADM1 versus CD7 plot accurately reflects disease progression in HTLV-I infection, and CADM1+ cells with downregulated CD7 in asymptomatic carriers have common properties with those in indolent ATLs. Clin Cancer Res; 20(11); 2851–61. ©2014 AACR.

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There has recently been an increase in data indicating that autoimmune mechanisms are involved in the etiopathogenesis of idiopathic thrombocytopenic purpura (ITP) (1, 2). Although antibodies that react with platelets are found in most patients with ITP, the pathogenetic nature of the antibodies remains to be clarified . The discovery of an animal model for ITP has therefore been long-awaited. Here we have found that (NZW x BXSB)Fi (W/B Fi) mice, which develop lupus nephritis with myocardial infarction (3), show thrombocytopenia with age, and that this is due to the presence ofboth platelet-associated antibodies (PAA) and circulating antiplatelet antibodies.Recently, we have demonstrated that allogeneic bone marrow transplantation (ABMT) has curative effects on autoimmune diseases in (NZB x NZW)FI, BXSB, MRL/MP-lpr/lpr (MRL/lpr), and NOD mice (4-6) . These results prompted us to examine whether ABMT can be used to treat ITP. In the present study, we provide evidence that the transplantation of bone marrow from BALB/c mice to W/B F, mice does indeed have preventative and curative effects on ITP Materials and MethodsMice.Mice ofthe inbred strain BALB/c nu/nu, BALB/c, C57B/6, C3H/HeN, BXSB, NZW were raised under specific pathogen-free conditions in our animal facility. W/B F, males were obtained from the Nippon Shinyaku Research Laboratories, Kyoto, Japan.Staining Procedure andData Analysis.Platelet-rich plasma was obtained as described previously (7) . The platelets were suspended in 1% paraformaldehyde solution for 5 min. After

This study investigates apoptosis as a mechanism for CD4+ T-cell depletion in human immunodeficiency virus type-1 (HIV-1) infection. Although several recent studies have shown that T cells of HIV-infected individuals show enhanced susceptibility to cell death by apoptosis, the mechanisms responsible for apoptosis are largely unknown. By using a flow cytometric technique and by morphology, we have quantitated the percentage of cells undergoing apoptosis in peripheral blood mononuclear cells (PBMCs) from HIV-seronegative donors and from HIV- infected asymptomatic patients. The PBMCs were cultured without any stimulus or with staphylococcus enterotoxin B, anti-T-cell receptor (TCR) alpha beta monoclonal antibody WT-31, or phytohemagglutinin for periods up to 6 days. In addition, we sought to determine whether cross- linking of CD4 followed by various modes of TCR stimulation in vitro could induce apoptosis in normal PBMCs. Here we show that (1) patient PMBCs undergo marked spontaneous apoptosis; (2) stimulation of T cells of patients as well as normal donors results in increased apoptosis; and (3) cross-linking of CD4 molecules is sufficient to induce apoptosis in CD4+ T cells if cross-linking is performed in unfractioned PBMCs, but not if CD4 molecules are cross-linked in purified T-cell preparations. These observations strongly suggest that accelerated cell death through apoptosis plays an important role in the pathogenesis of HIV-1 infection. At the same time, our observations implicate cross- linking of CD4 in vivo as a major contributor to this mechanism of accelerated cell death in HIV infection.