Epidermal growth factor receptor (EGFR) overexpression and activation are hallmarks of non-small cell lung carcinoma (NSCLC). Although EGFR-targeted therapies are used, the prognosis of NSCLC remains poor. ADAM17 induces activation of the EGFR through ligand cleavage. However, we show that inhibition or knockdown of ADAM17 markedly reduces tumorigenesis and survival to a large part independently from EGFR ligand shedding in NSCLC cells. These findings strongly indicate additional oncogenic mechanisms regulated by ADAM17. We identified Notch1 signaling as an

In this study we localized more precisely the salivary glycoprotein-interacting and the human immunoglobulin G (hIgG)-cross-reacting domains on the SR molecule, an antigen I/Il-related protein from S. mutans serotype f. Mapping of the SR molecule with polypeptides expressed by subclones covering the entire molecule and with synthetic peptides demonstrates that the salivary glycoprotein-binding domain is located in the N-terminal alanine-rich repeats of the SR molecule. In order to investigate the degree of conservation of both regions in various oral streptococci, we tested the reactivity of 8 representative strains of the mutans group and 11 nonmutans oral Streptococcus strains (S. anginosus, S. milleri, S. consteUlatus, S. intermedius, S. mitis, S. sanguis, S. gordonii, S. salivarius, and S. mitis strains) with antipeptide antibodies in a whole-cell enzyme linked immunosorbent assay together with colony hybridization analysis using DNA probes designed to map these two regions. All the mutans group strains except S. rattus and the 11 nonmutans streptococcal strains showed a high conservation of the C-terminal part of the SR molecule, especially the hIgG-cross-reacting domain, and less homology for the N-terminal salivary glycoprotein-binding region. Almost all of the sera from patients with rheumatic disease reacted strongly with SR from S. mutans serotype f, PI from S. mutans serotype c, and four peptides located in the hIgG-cross-reacting region and not with peptides located at the C and N termini and in the proline-rich repeats. These results confirm that epitopes located within this region are immunogenic in humans and could lead to the synthesis of natural anti-IgG antibodies.

Human hybridoma technologies permit the cloning of patient antibodies that may have desirable qualities. In this study, we report the isolation of a natural IgG antibody from a stomach cancer patient that illustrates novel diagnostic and therapeutic uses. Human antibody PAT-BA4 recognizes a tumor-specific variant of the transcription factor TATA-binding protein-associated factor 15 (TAF15) that is expressed on the plasma membrane of stomach cancer and melanoma cells but not healthy tissues. TAF15 is a member of the multifunctional TET protein family involved in mRNA transcription, splicing, and transport that is normally expressed only in the cytoplasm and nucleus of fetal or adult tissue cells. However, in malignant cells, TET family members including TAF15 seem to be involved in cell adhesion and spreading. In support of this likelihood, we found that PAT-BA4 inhibited tumor cell motility and tumor cell adhesion. Our findings define a role for a tumor-specific TAF15 antigen in malignant processes. Cancer Res; 70(1); 398-408.

1969 Poster Board I-992 Introduction: NPM/ALK is a constitutively activated, oncogenic kinase leading to the development of anaplastic large cell lymphoma in humans. Multiple pathways have been implicated in NPM/ALK-dependent signaling including STAT3 and STAT5. In a transgenic mouse model it could be demonstrated that STAT3 is critical for NPM/ALK-driven lymphomagenesis. However, deletion of STAT3 did not lead to prolonged survival of the mice. In addition, the role of STAT5 in NPM/ALK-positive lymphoma in vivo is largely unclear. Methods: We used the established murine bone marrow (BM) transplantation model using BM derived from STAT3 and STAT5 conditional knock-out (fl/fl) mice. Precisely, we harvested BM from STAT3fl/fl and STAT5fl/fl mice and expressed NPM/ALK-Cre/EGFP in the BM cells by using retroviral gene transfer. BM cells were transplanted in lethally irradiated wild-type mice. Expression of NPM/ALK and deletion of STAT3 and STAT5 was determined in BM cells. Results: BM from STAT3fl/fl and STAT5fl/fl mice was successfully harvested, retrovirally infected, and transplanted in recipient mice. Analysis of BM cells revealed expression of NPM/ALK and deletion of STAT3 or STAT5 in NPM/ALK-Cre/EGFP-infected STAT3fl/fl and STAT5fl/fl BM respectively. Within the STAT3 group, control mice transplanted with NPM/ALK-EGFP-infected STAT3fl/fl BM died after 2-3 weeks from a NPM/ALK-positive lymphoma. An additional control group transplanted with NPM/ALK-Cre/EGFP-transduced wild-type BM also died from a NPM/ALK lymphoma but with an increased latency. Notably, mice transplanted with NPM/ALK-Cre/EGFP-infected STAT3fl/fl (STAT3-deleted) BM showed a significantly prolonged survival compared to either control groups including 5 mice that survived at least 300 days after transplantation. Interestingly, only about 60% of these mice died from an NPM/ALK-positive high-grade lymphoma or myeloma-like disease, whereas the remaining animals died from other (irradiation-induced) diseases. In contrast, 150 days post transplantation STAT5 deletion in NPM/ALK expressing BM cells did not increase survival of the transplanted mice compared to the control group with wild-type BM using NPM/ALK-Cre/EGFP retrovirus. Conclusion: Specific deletion of STAT3 but not STAT5 in NPM/ALK-expressing cells markedly attenuates disease progression. The described transplantation model using BM from conditional knock-out mice and an Cre-containing expression vector is extremely helpful to specifically study signaling in oncogene-driven hematological malignancies. Disclosures: No relevant conflicts of interest to declare.