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Timakhov RA , Tan YF , Rao M , Liu ZM , Altomare DA , Pei JM , Wiest DL , Favorova OO , Knepper JE , Testa JR
Recurrent Chromosomal Rearrangements Implicate Oncogenes Contributing to T-Cell Lymphomagenesis in Lck-MyrAkt2 Transgenic Mice
Genes Chromosomes & Cancer. 2009 Sep;48(9) :786-794
PMCID: PMC 2739734   
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The oncogene v-akt was isolated from a retrovirus that induced naturally occurring thymic lymphomas in AKR mice. We hypothesized that constitutive activation of Akt2 could serve as a first hit for the clonal expansion of malignant T-cells by promoting cell survival and genomic instability, leading to chromosome alterations. Furthermore, genes that cooperate with Akt2 to promote malignant transformation may reside at translocation/inversion junctions found in spontaneous thymic lymphomas from transgenic mice expressing constitutively active Akt2 specifically in T cells. Cytogenetic analysis revealed that thymic tumors from multiple founder lines exhibited either of two recurrent chromosomal rearrangements, inv(6)(A2B1) or t(14;15)(C2;D1). Fluorescence in situ hybridization, array CGH, and PCR analysis were used to delineate the inv(6) and t(14;15) breakpoints. Both rearrangements involved T-cell receptor loci. The inv(6) results in robust upregulation of the homeobox/transcription factor gene D1x5 because of its relocation near the Tcrb enhancer. The t(14;15) places the Tcra enhancer in the vicinity of the Myc proto-oncogene, resulting in upregulated Myc expression. These findings suggest that activation of the Akt pathway can act as the initial hit to promote cell survival and genomic instability, whereas the acquisition of T-cell-specific overexpression of D1x5 or Myc leads to lymphomagenesis. (C) 2009 Wiley-Liss, Inc.
ISI Document Delivery No.: 475UB Timakhov, Roman A. Tan, Yinfei Rao, Mamta Liu, Zemin Altomare, Deborah A. Pei, Jianming Wiest, David L. Favorova, Olga O. Knepper, Janice E. Testa, Joseph R. WILEY-LISS