Abstract
Renal cell carcinoma (RCC) associated with Xp11.2 translocation (TFE3-RCC) has been recently defined as a distinct subset of RCC classified by characteristic morphology and clinical presentation. The Xp11 translocations involve the TFE3 transcription factor and produce chimeric TFE3 proteins retaining the basic helix-loop-helix leucine zipper structure for dimerization and DNA binding suggesting that chimeric TFE3 proteins function as oncogenic transcription factors. Diagnostic biomarkers and effective forms of therapy for advanced cases of TFE3-RCC are as yet unavailable. To facilitate the development of molecular based diagnostic tools and targeted therapies for this aggressive kidney cancer, we generated a translocation RCC mouse model, in which the PRCC-TFE3 transgene is expressed specifically in kidneys leading to the development of RCC with characteristic histology. Expression of the receptor tyrosine kinase Ret was elevated in the kidneys of the TFE3-RCC mice, and treatment with RET inhibitor, vandetanib, significantly suppressed RCC growth. Moreover, we found that Gpnmb (Glycoprotein nonmetastatic B) expression was notably elevated in the TFE3-RCC mouse kidneys as seen in human TFE3-RCC tumors, and confirmed that GPNMB is the direct transcriptional target of TFE3 fusions. While GPNMB IHC staining was positive in 9/9 cases of TFE3-RCC, Cathepsin K, a conventional marker for TFE3-RCC, was positive in only 67% of cases. These data support RET as a potential target and GPNMB as a diagnostic marker for TFE3-RCC. The TFE3-RCC mouse provides a preclinical in vivo model for the development of new biomarkers and targeted therapeutics for patients affected with this aggressive form of RCC. IMPLICATIONS: Key findings from studies with this preclinical mouse model of TFE3-RCC underscore the potential for RET as a therapeutic target for treatment of patients with TFE3-RCC, and suggest that GPNMB may serve as diagnostic biomarker for TFE3 fusion RCC.
Highlights
Xp11.2 translocation, t(X;1)(p11.2;q21.2), was first described in a pediatric renal cell carcinoma (RCC) case in 1986, and the fusion gene was confirmed to be PRCC-TFE3 in 1995 [1, 2]
PRCC-TFE3 cDNA was cloned into a targeting vector, pRosa26-DEST (Addgene plasmid # 21189; ref. 28), which has a LoxP-Stop-LoxP (LSL) cassette preceding the gene of interest, using the Gateway Protein Expression System according to the manufacturer's protocol
PRCC-TFE3 knockin mice, generated by inserting human PRCC-TFE3 cDNA preceded by a loxP-flanked neomycin cassette into the Rosa26 locus, were crossed with cadherin 16-Cre (KSPCre) transgenic mice to express PRCC-TFE3 in mouse kidney epithelial cells (Fig. 1A)
Summary
Xp11.2 translocation, t(X;1)(p11.2;q21.2), was first described in a pediatric renal cell carcinoma (RCC) case in 1986, and the fusion gene was confirmed to be PRCC-TFE3 in 1995 [1, 2]. TFE3 Xp11.2 translocation RCC (TFE3-RCC) was defined as an independent subtype of RCC by WHO in 2004 and is characterized by distinctive morphologic features and Xp11.2 rearrangements that create TFE3 gene fusions with a variety of partner genes TFE3 encodes a transcription factor that has a basic helix–loop–helix leucine zipper (bHLH-Zip) structure through which TFE3 dimerizes and interacts with M-box DNA sequences (TCAYRTGA) in transcriptional target genes. All TFE3 fusion genes encode in-frame chimeric proteins, which retain the bHLH-Zip domain of TFE3 [16, 18]. The evidence is strong for TFE3 fusions to be oncogenes with constitutively active transcriptional activity
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
