SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M some of these genes significantly correlates with DLBCL survival. An expressed sequence tag (EST) that the laboratory named human germinal center-associated lymphoma (HGAL) (UniGene cluster 49614 -Clone 814622,GI:2210537) was identified as a best predictor of DLBCL survival. The predictive power of HGAL was International Prognostic Indicator (IPI) independent, as demonstrated by multivariate analysis including components of the IPI. Furthermore, the prognostic power of HGAL expression in predicting survival was also shown when its expression was considered as a continuous variable demonstrating direct correlation between higher levels of its expression and longer survival. Higher HGAL expression in ABC-like DLBCL still predicted better overall survival. There was no difference in the complete response rates between patients with high and low HGAL expression, thus suggesting that high HGAL expression was associated with either better response to salvage treatment or lower relapse rates due to more complete tumor cell eradication or effective immunological surveillance. The laboratory has cloned the full-length cDNA of this EST from both sorted GC lymphocytes and from the Ramos cell line and termed the gene human germinal center-associated lymphoma (HGAL) (GenBank accession number AF521911). HGAL is located on chromosome 3q13. Comparison of the genomic sequence to the cDNA sequence revealed that HGAL spans 11kb. Recognition of a Kozak sequence and search for the longest open reading frame (ORF) led to the identification of a putative ORF extending from exon 1 to exon 6 and encoding a 178 amino acid protein, with 51 percent identity to the murine M17 protein that is expressed in GC lymphocytes. The HGAL gene product had a hydrophilic profile with no predicted transmembrane domain and lacked a nuclear localization sequence. HGAL contains a modified immunoreceptor tyrosine-based activation motif termed ITAM (D/EX 7 D/EX 2 YX 2 LX 7 YX 2 L) that plays a role in signal transduction in B and T lymphocytes. HGAL is not expressed in nonlymphoid tissues but is expressed at high levels only in GC lymphocytes, at intermediate levels in memory B cells, and at relatively low levels in peripheral blood B cells. In tumors, its expression is high in follicular lymphoma tumors, low in chronic lymphocytic leukemia cells, and heterogeneous in DLBCL specimens. Thus, HGAL expression may correlate with specific stages of B-cell differentiation, especially the GC stage. The function of HGAL in normal lymphocytes and the reason its expression in DLBCL correlates with better DLBCL outcome, are not known. Whether the improved survival of patients with high HGAL-content tumors is attributed to specific function of this gene or is a marker of important biologic characteristic of the tumor is unknown. Researchers in Dr. Lossos’ laboratory are currently investigating these questions. SELECTED PUBLICATIONS 2002 Lossos, IS , Or, R, Ginzburg, V, Christensen, TG, Mashriki, Y, and Breuer, R. Cyclosporin A upmodulates bleomycin-induced pulmonary fibrosis in BALB/c mice. Respiration 69:344-49, 2002. Auffermann-Gretzinger, S, Lossos, IS , Vayntrub, TA, Leong, W, Grumet, FC, Blume, KG, Stockerl-Goldstein, KE, Levy, R, and Shizuru, JA. Rapid establishment of dendritic cell chimerism in allogeneic hematopoietic cell transplant recipients. Blood 99:1442-48, 2002. Bokstein, F, Lossos, A, Lossos, IS, and Siegal, T. Central nervous system relapse of systemic non- Hodgkin’s lymphoma: results of treatment based on high-dose methotrexate combination chemotherapy. Leukemia & Lymphoma 43:587-93, 2002. UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 49
C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M Huang, JZ, Sanger, WG, Greiner, TC, Staudt, LM, Weisenburger, DD, Pickering, DL, Lynch, JC, Armitage, JO, Warnke, RA, Alizadeh, AA, Lossos, IS , Levy, R, and Chan, WC. The t(14;18) defines a unique subset of diffuse large B-cell lymphoma with a germinal center B-cell gene expression profile. Blood 99:2285-90, 2002. Lossos, IS , Thorstenson, YR, Wayne, TL, Oefner, PJ, Levy, R, and Chu, G. Mutation of the ATM gene is not involved in the pathogenesis of either follicle center lymphoma or its transformation to higher-grade lymphoma. Leukemia & Lymphoma 43:1079-85, 2002. Lossos, IS , Alizadeh, AA, Diehn, M, Warnke, R, Thorstenson, Y, Oefner, PJ, Brown, PO, Botstein, D, and Levy, R. Transformation of follicular lymphoma to diffuse large-cell lymphoma: Alternative patterns with increased or decreased expression of c-myc and its regulated genes. Proceedings of the National Academy of Sciences USA 99:8886-91, 2002. Lossos, IS , Warnke, R, and Levy, R. BCL-6 mRNA expression in higher grade transformation of follicle center lymphoma: correlation with somatic mutations in the 5' regulatory region of the BCL-6 gene. Leukemia 16:1857-62, 2002. Lossos, IS , Natkunam, Y, Levy, R, and Lopez, CD. Apoptosis stimulating protein of p53 (ASPP2) expression differs in diffuse large B-cell and follicular center lymphoma: correlation with clinical outcome. Leukemia & Lymphoma 43:2309-17, 2002. 2003 Lossos, IS , Alizadeh, AA, Rajapaksa, R, Tibshirani, R, and Levy, R. HGAL is a novel interleukin-4-inducible gene that strongly predicts survival in diffuse large B-cell lymphoma. Blood 101:433-40, 2003. Lossos, IS , Czerwinski, DK, Wechser, MA, and Levy, R. Optimization of quantitative real-time RT-PCR parameters for the study of lymphoid malignancies. Leukemia 17:789-95, 2003. Martinez-Climent, JA, Alizadeh, AA, Segraves, R, Blesa, D, Rubio-Moscardo, F, Albertson, DG, Garcia-Conde, J, Dyer, MJ, Levy, R, Pinkel, D, and Lossos, IS . Transformation of follicular lymphoma to diffuse large cell lymphoma is associated with a heterogeneous set of DNA copy number and gene expression alterations. Blood 101:3109-17, 2003. Akasaka, T, Lossos, IS , and Levy, R. BCL6 gene translocation in follicular lymphoma: a harbinger of eventual transformation to diffuse aggressive lymphoma. Blood 102:1443-48, 2003. Lossos, IS and Levy, R. Diffuse large B-cell lymphoma: insights gained from gene expression profiling. International Journal of Hematology 77:321-29, 2003. Lossos, IS and Levy, R. Higher grade transformation of follicular lymphoma: phenotypic tumor progression associated with diverse genetic lesions. Seminars in Cancer Biology 13:191-202, 2003. Lossos, IS , Akasaka, T, Martinez-Climent, JA, Siebert, R, and Levy, R. The BCL6 gene in B-cell lymphomas with 3q27 translocations is expressed mainly from the rearranged allele irrespective of the partner gene. Leukemia 17:1390-97, 2003. Do, B, Lossos, IS , Thorstenson, Y, Oefner, PJ, and Levy, R. Analysis of FAS (CD95) gene mutations in higher-grade transformation of follicle center lymphoma. Leukemia & Lymphoma 44:1317-23, 2003 Lossos, IS , Akasaka, T, and Levy, R. Multiple BCL6 translocation partners in individual cases of gastric lymphoma. Blood 102:1931-32, 2003. 50 UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
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SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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