Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation.
MITF, TFE3, TFEB, and TFEC comprise a transcription factor family (MiT) that regulates key developmental pathways in several cell lineages. Like MYC, MiT members are basic helix-loop-helix-leucine zipper transcription factors. MiT members share virtually perfect homology in their DNA binding domains and bind a common DNA motif. Translocations of TFE3 occur in specific subsets of human renal cell carcinomas and in alveolar soft part sarcomas. Although multiple translocation partners are fused to TFE3, each translocation product retains TFE3's basic helix-loop-helix leucine zipper. We have identified the genes fused by the chromosomal translocation t(6;11)(p21.1;q13), characteristic of another subset of renal neoplasms. In two primary tumors we found that Alpha, an intronless gene, rearranges with the first intron of TFEB, just upstream of TFEB's initiation ATG, preserving the entire TFEB coding sequence. Fluorescence in situ hybridization confirmed the involvement of both TFEB and Alpha in this translocation. Although the Alpha promoter drives expression of this fusion gene, the Alpha gene does not contribute to the ORF. Whereas TFE3 is typically fused to partner proteins in subsets of renal tumors, we found that wild-type, unfused TFE3 stimulates clonogenic growth in a cell-based assay, suggesting that dysregulated expression, rather than altered function of TFEB or TFE3 fusions, may confer neoplastic properties, a mechanism reminiscent of MYC activation by promoter substitution in Burkitt's lymphoma. Alpha-TFEB is thus identified as a fusion gene in a subset of pediatric renal neoplasms.
Davis
Ian J
IJ
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Hsi
Bae-Li
BL
Arroyo
Jason D
JD
Vargas
Sara O
SO
Yeh
Y Albert
YA
Motyckova
Gabriela
G
Valencia
Patricia
P
Perez-Atayde
Antonio R
AR
Argani
Pedram
P
Ladanyi
Marc
M
Fletcher
Jonathan A
JA
Fisher
David E
DE
D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D002896:Chromosomes, Human, Pair 6; D003001:Cloning, Molecular; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D015321:Gene Rearrangement; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D007438:Introns; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics; D014178:Translocation, Genetic; D014410:Tumor Stem Cell Assay
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D017931:DNA Primers; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C069203:TFE3 protein, human; C064972:TFEB protein, human; D014157:Transcription Factors