Livin Expression in Normal Hematopoietic Cells and in Hematologic Malignancies.

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<0.05). On the other hand, Livin was not expressed in Hodgkin’s disease (4 pts and 4 cell lines) and only 6/29 pts with AML had high levels of Livin in RT-PCR without any clinical correlation. Our data demonstrate that Livin is over expressed in activated normal B cells both in peripheral blood and LN as well as in most B cell lymphoproliferative diseases. Further investigation will establish the role of Livin over expression in hematologic malignancies.