Vascular endothelial growth factor (VEGF) and interleukin-8/CXCL8 (IL-8) are prominent pro-angiogenic and pro-metastatic proteins that represent negative prognostic factors in many types of cancer. Hypoxia is thought to be the primary environmental cause of VEGF and IL-8 expression in solid tumors. We hypothesized that a lack of nutrients other than oxygen could stimulate the expression of these factors and previously demonstrated that expression of VEGF and IL-8 is responsive to amino acid deprivation. In the present study, we examined the effect of glutamine availability on the expression of these factors as well as the role of transcription factors NFB and activating protein-1 (AP-1) in the response of TSE human breast carcinoma cells to glutamine deprivation. VEGF and IL-8 secretion and mRNA levels were dramatically induced by glutamine deprivation. mRNA stabilization contributed to this response.

Background: The expression of pro-angiogenic cytokines, such as vascular endothelial growth factor (VEGF) and interleukin-8/CXCL8 (IL-8), plays an important role in tumor growth and metastasis. Low oxygen tension within poorly-vascularized tumors is thought to be the prime stimulus causing the secretion of VEGF. The expression of IL-8 by solid tumors is thought to be primarily due to intrinsic influences, such as constitutive activation of nuclear factor kappa B (NF-κB). However, VEGF expression is responsive to glucose deprivation, suggesting that low concentrations of nutrients other than oxygen may play a role in triggering the pro-angiogenic phenotype. Glucose deprivation causes endoplasmic reticulum (ER) stress and alters gene expression through the unfolded protein response (UPR) signaling pathway. A branch of the UPR, known as the ER overload response (EOR), can cause NF-κB activation. Thus, we hypothesized that treatments that cause ER stress and deprivation of other nutrients, such as amino acids, would trigger the expression of angiogenic cytokines by breast cancer cell lines.

The basis for persistence of leukemic stem cells in the bone marrow microenvironment (BMME) remains poorly understood. We present evidence that signaling crosstalk between α4 integrin and Abelson interactor-1 (Abi-1) is involved in acquisition of an anchorage-dependent phenotype and drug resistance in Bcr-Abl positive leukemia cells. Comparison of Abi-1 (ABI-1) and α4 integrin (ITGA4) gene expression in relapsing Bcr-Abl positive CD34+ progenitor cells demonstrated a reduction in Abi-1 and an increase in α4 integrin mRNA in the absence of Bcr-Abl mutations. This inverse correlation between Abi-1 and α4 integrin expression, as well as linkage to elevated phospho-Akt and phospho-Erk signaling, was confirmed in imatinib mesylate (IM) resistant leukemic cells. These results indicate that the α4-Abi-1 signaling pathway may mediate acquisition of the drug resistant phenotype of leukemic cells.

4864 Introduction: We report a case of PNP in a patient who was subsequently diagnosed with classical Hodgkins Lymphoma mixed cellularity type. PNP is an autoimmune mediated blistering disorder that presents with skin lesions demonstrating characteristics of erythema multiforme and pemphigus vulgaris. Case: A 76 year-old Hispanic male presented to the Emergency department with intermittent low fevers of 4 months duration associated with progressive weakness and fatigue; he now had mouth ulcers of 1-week duration along with anorexia. Physical exam was significant for a temperature of 102.4F, bilateral conjunctivitis with mild white discharge. Labs included WBC 5,000/mm3, hemoglobin 9.5 gm/dL, platelets 99,000/mm3; differential showed lymphocytes 22%, monocytes 11%, eosinophils 3%, and myelocytes 9%. Oral examination revealed dry mucosa with bleeding perioral ulcers. An ulcer biopsy was obtained and demonstrated necrotic keratinocytes and necrotic neutrophilic inflammation consistent with PNP. Chest CT showed a multinodular goiter, enlarged mediastinal and hilar nodes with calcified granulomas bilaterally as well as a new noncalcified nodule in the right lung. PET scan revealed FDG avid lymph nodes in the left supraclavicular, hilar and left axilla areas as well as multiple regions in the spleen and retroperitoneal nodes. A left axillary node biopsy showed classical Hodgkins lymphoma of mixed cellularity type. The patient was started on prednisone 75 mg per day in divided doses and his oral ulcerations and clinical status improved after 2 days of therapy. Subsequently the patient was started on gemcitabine, vinorelbine and liposomal doxorubicin (GVD) chemotherapy for his malignancy. Discussion: Although PNP has been described as being associated with hematologic malignancies such as Non-Hodgkins Lymphoma, Chronic Lymphocytic Leukemia and Castleman's disease, it has rarely been demonstrated in association with classical Hodgkins disease. This case report highlights the need for a higher index of suspicion of underlying malignancy including classical Hodgkins disease when confronted with a patient presenting PNP. Disclosures: No relevant conflicts of interest to declare.