598

BCL2L1

BCL-XL/S|BCL2L|BCLX|BCLXL|BCLXS|Bcl-X|PPP1R52|bcl-xL|bcl-xS;BCL2-like 1;BCL2L1;BCL2-like 1

apoptosis regulator Bcl-X|bcl-2-like protein 1|protein phosphatase 1, regulatory subunit 52

20q11.21

protein-coding

PURPOSE: Apoptosis plays a crucial role in normal development and mediates tumorresponse to chemotherapy. This study investigated the pattern of apoptotic gene expression in brain tumor tissue specimens and cell lines. MATERIALS AND METHODS: BCL2, BCLXL, BCLXS, and BAX transcripts were amplified using reverse transcriptase polymerase chain reaction in 7 high-grade gliomas (HGGs), 7 ependymomas, and 6 cell lines (2 glioblastomas, 3 medulloblastomas, and 1 supratentorial-primitive neuroectodermal tumor [PNET]). Immunohistochemical staining for BCL2, BCLX, BAX, and p53 was performed in 7 pediatric low-grade gliomas (LGGs) and 7 pediatric HGGs. RESULTS: Six of seven gliomas, ALL ependymomas, and ALL glioblastoma and medulloblastoma cell lines expressed BCLXLand BAX. BCL2 expression was only detected in the supratentorial PNET line PFSK.BCLXS was absent in ALL tumors. By immunohistochemistry, no glial tumors stainedpositively for BCL2. Similar BAX and BCLX protein expression was observed in LGGand HGG. Three of five glioblastomas showed significant p53 expression. CONCLUSIONS: Coexpression of proapoptotic and antiapoptotic genes in human braintumors supports the hypothesis that the relative expression of competing genes determines apoptotic threshold.

PURPOSE: Retinoblastoma is a malignant tumor that usually develops in early childhood. During retinoblastoma spreading, RB1 gene inactivation is followed byadditional genomic modifications which progressively lead to resistance of tumorcells to death. Drugs that act at downstream levels of death signaling pathways should therefore be interesting in killing retinoblastoma cells. ABT-737, a BH3 mimetic molecule effective at the mitochondrial level, has been shown to induce apoptosis in different human tumoral cell lines as well as in primary patient-derived cells, and in a mouse xenograph model. METHODS: In this report, we analyzed the pro-death effect of ABT-737 on two human retinoblastoma cell lines, Y79 and WERI-Rb, as well as on the mouse photoreceptor cell line 661W. RESULTS: We observed that ABT-737 was very effective as a single agent in inducing human WERI-Rb cells apoptosis without affecting the mouse 661W photoreceptor cells. However human Y79 cells were resistant to ABT-737, as a probable consequence of the absence of Bax. The high sensitivity of WERI-Rb to ABT-737 can be increased by downregulating Mcl-1 using the proteasome inhibitor MG-132. Preliminary analysis in primary mouse retinoblastoma tumoral cell lines predicts high sensitivity to ABT-737. CONCLUSION: Our data suggest that ABT-737 or related compounds could be a highly effective drug in the treatment of some retinoblastomas.