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Cloning of an Alpha-TFEB Fusion in Renal Tumors Harboring the T(6;11)(P21;Q13) Chromosome Translocation

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Cloning of an Alpha-TFEB Fusion in Renal Tumors Harboring the T(6;11)(P21;Q13) Chromosome Translocation Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation Ian J. Davis*†, Bae-Li Hsi‡, Jason D. Arroyo*, Sara O. Vargas§, Y. Albert Yeh§, Gabriela Motyckova*, Patricia Valencia*, Antonio R. Perez-Atayde§, Pedram Argani¶, Marc Ladanyiʈ, Jonathan A. Fletcher*‡, and David E. Fisher*†** *Department of Pediatric Oncology, Dana–Farber Cancer Institute, Boston, MA 02115; Departments of †Medicine and §Pathology, Children’s Hospital Boston, Boston, MA 02115; ‡Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115; ʈDepartment of Pathology, Memorial Sloan–Kettering Cancer Center, New York, NY 10021; and ¶Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD 21287 Communicated by Phillip A. Sharp, Massachusetts Institute of Technology, Cambridge, MA, March 12, 2003 (received for review January 28, 2003) MITF, TFE3, TFEB, and TFEC comprise a transcription factor family Among members of the MiT family, TFE3 has previously been (MiT) that regulates key developmental pathways in several cell implicated in cancer-associated translocations. TFE3 transloca- lineages. Like MYC, MiT members are basic helix-loop-helix-leucine tions occur in distinctive renal carcinomas of childhood and zipper transcription factors. MiT members share virtually perfect young adults and in alveolar soft part sarcoma. In these trans- homology in their DNA binding domains and bind a common DNA locations, the DNA binding domain of TFE3 is fused to various motif. Translocations of TFE3 occur in specific subsets of human N-terminal partners, including PRCC, NonO (p54nrb), PSF, or renal cell carcinomas and in alveolar soft part sarcomas. Although ASPL (15–20). Although the mechanism through which these multiple translocation partners are fused to TFE3, each transloca- fusions contribute to oncogenesis remains unclear, several stud- tion product retains TFE3’s basic helix–loop–helix leucine zipper. ies suggest that the PRCC-TFE3 (21, 22) and ASPL-TFE3 fusion We have identified the genes fused by the chromosomal translo- proteins (M.L., unpublished observations) are transcriptional cation t(6;11)(p21.1;q13), characteristic of another subset of renal activators. One study explored the possibility that PRCC-TFE3 neoplasms. In two primary tumors we found that Alpha,an may interfere with mitotic checkpoint control via the PRCC intronless gene, rearranges with the first intron of TFEB, just domain (23), although it is unclear whether such a mechanism MEDICAL SCIENCES upstream of TFEB’s initiation ATG, preserving the entire TFEB could apply to the other fusion partners. coding sequence. Fluorescence in situ hybridization confirmed the Recently a class of renal tumors containing a novel involvement of both TFEB and Alpha in this translocation. Al- t(6;11)(p21.1;q12) translocation has been described (24). though the Alpha promoter drives expression of this fusion gene, Whereas these tumors exhibit epithelioid morphology suggestive the Alpha gene does not contribute to the ORF. Whereas TFE3 is of renal carcinoma, they are distinctive in their non- typically fused to partner proteins in subsets of renal tumors, we immunoreactivity for epithelial markers (cytokeratin, epithelial found that wild-type, unfused TFE3 stimulates clonogenic growth membrane antigen) and positive immunoreactivity for melano- in a cell-based assay, suggesting that dysregulated expression, cytic markers (HMB45, MelanA). We report here that TFEB is rather than altered function of TFEB or TFE3 fusions, may confer targeted by this translocation in both of two tumors examined. neoplastic properties, a mechanism reminiscent of MYC activation TFEB fuses with the Alpha gene at 11q13, an intronless gene that by promoter substitution in Burkitt’s lymphoma. Alpha-TFEB is does not contribute coding sequence to the fusion product. thus identified as a fusion gene in a subset of pediatric renal Furthermore, hypothesizing that dysregulated expression may neoplasms. contribute to the oncogenic mechanism for TFE3 and TFEB, we demonstrate that constitutive expression of wild-type, unfused ITF, TFE3, TFEB, and TFEC are closely related basic TFE3 can rescue melanoma clonogenic growth in response to Mhelix–loop–helix leucine zipper (bHLH-LZ) transcription inhibition of Wnt signaling. factors (1–8) that may homo- or heterodimerize in all combi- nations to bind DNA (9). These factors share sequence homol- Materials and Methods ogy in their DNA-contacting basic domains (10), as well as Clinical History. The index case was an 18-yr-old female with a activation domains, and recognize identical DNA sequences (9), history of obesity, hirsutism, and polycystic ovary syndrome. A suggesting that they may regulate similar downstream targets. right renal mass was detected, and partial nephrectomy was Genetic and biochemical studies have revealed functional over- performed. The patient was well, without evidence of recurrent lap of MiT activity in certain developmental lineages. Specifi- neoplastic disease at 18-mo follow-up. Postoperatively, she con- cally, use of knockout mice by Jenkins and colleagues (8) has tinued to require spironolactone for control of hirsutism. Clin- elegantly demonstrated that, whereas mutation of either Mitf or ical details of the second patient, an 18-yr-old male with a 7-cm TFE3 in mice does not disrupt osteoclast development, mutation left renal mass, are published (24). of both genes or presence of a dominant-negative allele produces severe osteopetrosis. Homozygous mutation of MITF in the Pathologic Examination. Portions of tumor from a partial nephrec- mouse is particularly devastating to the melanocyte lineage, tomy performed on the index patient were immediately placed resulting in failure of melanocyte development (5). In humans, in 2% glutaraldehyde for ultrastructural analysis, in antibiotic- Mitf haploinsufficiency results in type IIa Waardenburg syn- enriched cell culture medium for cytogenetic analysis, in OCT drome (11). Mice homozygous null for TFE3 or TFEC had no compound for Ϫ60°C storage, and in 10% buffered formalin for recognized abnormalities (8), but TFEB nulls exhibited embry- histologic evaluation. Paraffin-embedded sections were stained onic lethality associated with placental vascular defects (12). In with hematoxylin and eosin (H&E) and Hale’s colloidal iron. addition, Mitf and TFE3 have been found to undergo identical modifications after cytokine stimulation (13), and MITF has been shown to directly regulate BCL2, a key apoptotic regulator, Abbreviations: bHLH-LZ, basic helix–loop–helix leucine zipper; H&E, hematoxylin and in a manner important for melanocyte and melanoma survi- eosin; FISH, fluorescence in situ hybridization; BAC, bacterial artificial chromosome. val (14). **To whom correspondence should be addressed. E-mail: david࿝fi[email protected]. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0931430100 PNAS ͉ May 13, 2003 ͉ vol. 100 ͉ no. 10 ͉ 6051–6056 Downloaded by guest on September 30, 2021 Immunohistochemical staining was performed on formalin- fixed paraffin-embedded material by using a streptavidin-biotin- based alkaline phosphatase detection kit (universal multispecies USA horseradish peroxidase kit; Signet Laboratories, Dedham, MA) with liquid DAB-plus (Zymed). The following antibodies were used: HMB-45, monoclonal S100, desmin (BioGenex Lab- oratories, San Ramon, CA), epithelial membrane antigen, AE1- AE3, chromogranin (Signet Laboratories), low-molecular- weight cytokeratin (CAM 5.2; Becton Dickinson), CD10 (Cell Marque, Hot Springs, AR), and vimentin clone V-9 (DAKO). Positive and negative controls were stained in parallel. Glutaraldehyde-fixed tissue was postfixed in osmium tetroxide and embedded in Epon 812. One-micrometer-thick sections were stained with toluidine blue and examined microscopically to confirm the presence of tumor. Ultrathin sections were stained with uranyl acetate and lead nitrate and examined with a Philips 300 electron microscope (Philips, Eindhoven, The Netherlands). Gross examination of the right upper kidney pole revealed a well-circumscribed tan-yellow homogeneous 2.8 ϫ 2.5 ϫ 2.5-cm mass distending the renal capsule. Histologically, the tumor consisted of epithelioid cells arranged in a nested alveolar or acinar pattern (Fig. 1A). In areas, these acini were elongated and irregular, imparting a papillary-like appearance to the architec- ture. Acinar lumens often contained clusters of degenerating cells with pyknotic nuclei. Rare ‘‘blood lakes’’ were identified. Individual cells were round-to-polygonal with abundant cyto- plasm. Cells with eosinophilic granular cytoplasm and cells with clear cytoplasm were interspersed, with the eosinophilic cells being generally more basally located (Fig. 1B). Nuclei were round and often showed nucleoli that were conspicuous at low power, corresponding to a Fuhrman nuclear grade 3 of 4. Rare foci of psammomatous calcification were present. Foam cells, hyaline globules, and hemosiderin were not identified. Nests were nearly back-to-back, separated by thin capillary-sized vas- cular channels. Positive staining for colloidal iron, HMB-45 (focal, rare; Fig. 1C), CD10, and vimentin was observed. Tumor cells were negative for AE1͞AE3, Cam5.2, epithelial membrane antigen, S100, chromogranin, and desmin. The tumor was en- compassed by a fibrous capsule (which lacked calcification), did not involve the renal sinus, and corresponded to a NWTS-5 stage I (National Wilms Tumor Study Group, 2001). Ultrastructural examination showed that the granular cells
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