Search

Livin is a member of the Inhibitor of Apoptosis Proteins (IAP) family, a novel family of intracellular anti-apoptotic proteins that act by binding and inhibiting caspases. We found that Livin is unique among the IAP members as upon strong apoptotic stimuli, it is specifically cleaved by caspases to produce a large C-terminal subunit. This subunit has a paradoxical pro-apoptotic activity. Thus, Livin is not merely an inhibitor of apoptosis. Rather, it is a regulator of apoptosis that can protect against apoptosis but upon continuous apoptotic signals it helps to assure cell death. We showed that Livin plays a major role in melanoma. The level of the Livin protein is directly correlated to the resistance of melanoma cells to chemotherapy and to the survival rate of melanoma patients. Livin was also shown to be over expressed in other solid tumors such as nasopharyngeal, neuroblastoma, colorectal and lung cancers. In this work we studied Livin expression in normal hematopoietic cells as well as hematologic malignancies. Using immunohistochemistry staining for Livin we evaluated its expression in reactive lymph nodes (LN) and showed that in contrast to Bcl2, Livin was detected in highly proliferating germinal centers. In normal bone marrow Livin was detected in Megakaryocytes and immature myeloid precursors. In peripheral blood mononuclear cells, using quantitative RT-PCR, we found that Livin expression was down regulated in activated monocytes and T cells while in B cells, Livin was upregulated upon activation. We studied bone marrow and LNs from 84 patients (pts) with hematologic malignancies. Positive immunohistochemistry staining was found in the malignant cells of all pts with DLBC NHL (31 pts), follicular lymphoma (12 pts) and multiple myeloma (15 pts). Peripheral blood samples from 28 B-CLL pts were compared with healthy controls’ B cells. High mRNA levels were detected in 43% of the pts, in correlation with older age (p

Recent effort in the molecular characterization of diffuse large B-cell lymphoma (DLBCL) has led to the recognition that patients with DLBCL of germinal center origin exhibit a better overall survival. Thus, identification and characterization of markers of germinal center derivation are of importance in dissecting prognostic subclasses of DLBCL. The VICKZ (Vg1 RBP/Vera, IMP1, 2, 3, CRD-BP, KOC, ZBP-1) family members are RNA-binding proteins that recognize specific RNA targets and have been implicated in diverse cellular functions including cell polarity, migration, proliferation and tumorigenesis/metastasis. We generated an antibody that recognizes all three isoforms of VICKZ protein and characterized its expression in normal lymphoid tissue and in lymphoma subtypes. In normal tonsils, VICKZ protein showed a germinal center-specific pattern of expression with staining localized to the cytoplasm. Among 868 non-Hodgkin and Hodgkin lymphomas tested by immunohistochemistry on tissue microarrays, staining for VICKZ protein was present in 76% (126/165) of follicular lymphoma, 78% (155/200) of DLBCL, 90% (9/10) of mediastinal large B-cell lymphoma, and 100% (2/2) of Burkitt lymphoma. A subset of mantle cell lymphoma (11%, 2/19), extranodal (8%, 2/25), and nodal (20%, 1/5) marginal zone lymphoma and lymphoblastic lymphoma (25%, 4/13), showed VICKZ staining. The majority of lymphocyte predominant Hodgkin (92%, 12/13) and classical Hodgkin (94%, 101/108) lymphoma were found to be positive. Among T cell lymphoma, anaplastic large cell lymphoma were positive (75%, 6/9). Additional work is in progress to correlate VICKZ protein expression with other germinal center markers such as HGAL, BCL6 and CD10 as well as with prognostic subclasses of DLBCL. The differential expression pattern of VICKZ protein in lymphoma subtypes suggests a potential utility for VICKZ in the identification of subgroups of DLBCL associated with different prognoses.