Recurrent chromosomal rearrangements implicate oncogenes contributing to T-cell lymphomagenesis in Lck-MyrAkt2 transgenic mice.
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 Dlx5 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 Dlx5 or Myc leads to lymphomagenesis.
Timakhov
Roman A
RA
Human Genetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Tan
Yinfei
Y
Rao
Mamta
M
Liu
Zemin
Z
Altomare
Deborah A
DA
Pei
Jianming
J
Wiest
David L
DL
Favorova
Olga O
OO
Knepper
Janice E
JE
Testa
Joseph R
JR
D000818:Animals; D001483:Base Sequence; D002869:Chromosome Aberrations; D019457:Chromosome Breakage; D055028:Comparative Genomic Hybridization; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics*; D016399:Lymphoma, T-Cell / Q000201:enzymology / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009857:Oncogenes; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D016415:Sequence Alignment; D014407:Tumor Cells, Cultured
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt