Genomic alteration in hematologic malignancies and their roles for proliferation and differentiation

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1.MALT lymphoma related genes for cell differentiation and proliferation :MALT1, BCL10 (B-cell lymphoma 10), and API2 (apoptosis inhibitor 2)-MALT1 are key molecules in mucosa-associated lymphoid tissue (MALT) lymphomagenesis. We previously reported that MALT1 and API2- MALT1 were localized only in cytoplasm, where we suggested that both molecules were likely to be active. We examined the localization-determining region by generating various mutants and were able to demonstrate that there were nuclear export signal (NES)-containing domains in the MALT1 C-terminal region. The use of leptomycin B, an NES-specific inhibitor, demonstrated that both MALT1 and API2- MALT1 were predominantly retained in the nuclei, indicating that these molecules were shuttling between nucleus and cytoplasm in an NES-dependent manner.2.Genomic alterations in malignant lymphoma :Diffuse large B-cell lymphoma (DLBCL) comprises molecularly distinct subgroups such as activated B- cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL. We previously reported that CD5+ and CD5-CD10+DLBCL constitute clinically relevant subgroups. To determine whether these two subgroups are related to ABC and GCB DLBCL, we analyzed the genomic imbalance of 99 cases using array-CGH. 46 of these cases were subsequently subjected to gene expression profiling. A comparison of genome profiles of distinct subgroups of DLBCL demonstrated specific genomic alterations to each subtype. We have also analyzed Mantle cell lymphoma (MCL) with array CGH technology and found MCL specific genomic alterations. In MCL 2q13 homologous deletion was found in addition to recurrent heterozygous losses. The target gene was found to be BIM1, an antagonist of BCL2, suggesting a role for MCL lymphomagenesis.