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Adult T-cell leukemia (ATL) occurs in human T-lymphotropic virus type I-infected individuals and is endemic to the southwestern area of Kyushu in Japan. Here, we found that nM levels of genistein and 17β-estradiol had cytotoxic effects on ATL cells and activated caspase-3. The estrogen receptor antagonist ICI182780 negated the cytotoxic effect of genistein. In addition, G protein-coupled estrogen receptor agonist G-1 also had a cytotoxic effect on ATL cells. This is the first report suggesting that estrogen receptors are a molecular target for ATL therapy.

A 42-year-old female with a mediastinal tumor and massive pleural effusion ws admitted to our hospital in June 1993. Biopsy revealed lymphoblastic lymphoma. She had no evidence of distant metastasis except pleural effusion. Bone marrow examination revealed a normal karyotype (46, XY). The patient had been progression-free for more than 1 year after achieving complete remission by induction, consolidation and maintenance therapy according to the standard chemotherapy and involved-field radiation for lymphoblastic lymphoma. From May 1996 progressive leukopenia and thrombocytopenia developed. The diagnosis of refractory anemia with excess of blasts (RAEB) was made. Subsequently, in November 1996, she developed acute myelogenous leukemia (AML), M4 type by FAB classification. The karyotype of MDS and AML clones involved inversion (3) (q21q26) and monosomy 7. The EVI 1 gene was examined and was proved to be rearranged and activated. This may be the first case among the therapy-related cases of MDS/AML reported whose karyotypes were followed and in which the mRNA expression of EVI 1 gene involved was directly proved in the leukemogenesis process of chemotherapy-induced secondary MDS and AML.

Background Human T-cell lymphotropic virus (HTLV-1) is a retrovirus endemic in Latin America, Africa, and Asia. Increasing numbers are being reported in the United States. HTLV-1 causes Adult T-cell Leukemia/Lymphoma (ATL) in 3–5% of HTLV-1 carriers, usually only after a prolonged latent period. Co-infection with the nematode Strongyloides stercoralis (SS) is associated with early onset of ATL. The exact mechanism by which SS accelerates ATL development in HTLV-1 subjects is not understood. CADM1 has been recently identified as a surface marker of HTLV-1 infected cells; CD7 is a probable marker of early cell transformation. We hypothesize that previous SS infection will increase the proportion of infected T cells (CADM1+) and lead to transformation of infected cells (CADM1+CD7low) in HTLV-1 subjects. Methods In this pilot study, we tested seven subjects that were diagnosed with HTLV-1 between 2006 and 2008 and actively followed up at the HTLV-1 Cohort Clinic at the Tropical Medicine Institute in Lima, Peru. Five had previous SS infection. We performed surface flow cytometry staining of peripheral blood mononuclear cells with monoclonal antibodies against CADM1, CD7, CD4, and CD3. Current SS infection was ruled out by the Baermann technique in a stool sample. Results Average age was 53 years (range 30–79). Average time since diagnosis of HTLV-1 was 10 years (range 9–11). One 30-year-old patient with prior SS infection was diagnosed with ATL and hospitalized in the ICU at the time of follow-up and excluded from group comparison. There was a trend for higher proportions of CADM1+ T-cells in subjects with previous SS co-infection compared with those without SS (median 16.20% vs. 9.55%, P = 0.13, Mann–Whitney). The proportion of PBMCs that were CADM1+CD7− was also increased in some of those with previous SS (Figure 1). Conclusion Our pilot data suggest that SS co-infection is associated with prolonged effects on HTLV-1 infection. We noted trends towards increased numbers of HTLV-1 infected cells (CADM1+) and a predisposition towards malignant transformation (CADM1+CD7low). Further studies are needed to confirm this observation and to determine whether CADM1 and CD7 expression may be useful as a screening tool to monitor HTLV-1 subjects at high risk of developing ATL. Figure 1. Representative flow cytometry. Disclosures All authors: No reported disclosures.

Interleukin 3 (IL-3) is a growth factor that supports the proliferation of early hematopoietic stem cells, as well as cells that are committed to a variety of the myeloid lineages. The mechanisms by which IL-3 functions have been studied through the use of a series of IL-3-dependent cell lines isolated from myeloid leukemias or long-term bone marrow cultures. A variety of studies have implicated tyrosine phosphorylation in IL-3 signal transduction. One of the substrates of phosphorylation is a 140 kDa, IL-3-binding protein that is speculated to be the biologically relevant IL-3 receptor. IL-3, through tyrosine phosphorylation, supports viability and growth through the regulation of transcription of a series of genes including c-myc and c-pim-1. The c-myc gene contributes to viability, in part, by regulating the transcription of the ornithine decarboxylase gene. The role of growth factors in differentiation is less clear. By studying IL-3-dependent myeloid leukemia cell lines, two genes have been identified whose altered expression is associated with blocking the ability of the cells to differentiate. The c-myb gene is a nuclear DNA binding protein that has been implicated in myeloid transformation in a number of systems. The Evi-1 gene is a novel gene of the zinc finger family of transcriptional activators. Possible mechanisms by which these genes interfere with normal differentiation are discussed.

BACKGROUND: Ecotropic viral integration site 1 (EVI1) gene encodes a transcription factor, containing ten zinc finger motifs found within two domains of the protein. Abnormal expression of EVI1 is found in 5-10% of patients with acute myeloid leukemia (AML), and is associated with unfavorable outcome. EVI1 maintains the self-renewal capacity of hematopoietic stem cells (HSCs), of cell quiescence and stem cell-like phenotypes in leukemia cells. EVI1 knocked out mice die approximately 10.5 days post-coitus (d.p.c.; E10.5) with defect or hypoplasty in heart, cranial ganglia, peripheral nervous system. It is possible that EVI1 also regulates the fate of neural stem cells (NPCs) and glioma initiating cells (GICs) as well as HSCs. METHODS: We investigated the biological effect of knockdown and overexpression of EVI1 against NPCs and GICs. RESULTS: We found that NPCs from nestin-cre induced EVI1 (-/-) mouse differentiated to neuron and glial cells earlier than wild type NPCs. Notch signals were altered in EVI1 (-/-) NPCs. Knockdown experiment with shEVI1 in GICs showed the monolayerd GICs hard to stick to laminin-coated dish by alteration of integrin signals. Because laminin is a major component of niche of NPCs and GICs, EVI1 has an important role to maintain the stem cell capacity by committing to niche. Moreover overexpression of EVI1 in U87 MG and GICs decreased cell proliferation. CONCLUSIONS: Taken together, EVI1 regulates the cell fate and proliferation of NPCs and GICs. SECONDARY CATEGORY: n/a.