Identification of potential therapeutic targets for precursor T-cell leukemia/lymphoma using gene expression profiling Free

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An improved understanding of leukemogenic pathways could lead to development of more effective and less toxic therapy. Gene expression profiling has been employed to identify genes that show altered expression patterns in malignant cells compared to the malignant cells normal counterpart as these genes may be important for malignant transformation. Therefore, we compared the gene expression pattern of thymic tumors from precursor T-cell lymphoblastic lymphoma/leukemia (pre-T LBL) that arose in transgenic mice which overexpressed SCL, LMO1, or NUP98-HOXD13 (NHD13) with that of thymocytes from normal littermates. Only two genes, Ccl8 and Mrpl38 were consistently more than 4-fold overexpressed, and a single gene, Prss16 was consistently underexpressed in a panel of 26 pre-T LBL samples. However, we identified a number of genes, such as Cfl1, Tcra, Tcrb, Pbx3, Eif4a, Eif4b, and Cox8b that were over or under-expressed in pre-T LBL that arose in specific lines. Similar to the situation seen with human pre-T LBL, the SCL/LMO1 leukemias displayed an expression profile consistent with mature, late cortical thymocytes, whereas the NHD13 leukemias displayed an expression profile more consistent with immature thymocytes. We evaluated two of the most differentially regulated genes as potential therapeutic targets. Cfl1 was specifically overexpressed in SCL-LMO1 tumors and inactivation of Cfl1 using Okadaic acid resulted in suppression of leukemic cell growth. Overexpression of Ccl8 was a consistent finding in pre-T LBL that arose in all 3 transgenic lines, and an antagonist for the Ccl8 receptor induced death of leukemic cell lines, suggesting a novel therapeutic approach for pre-T LBL.