Intragenic beta-synuclein rearrangements in malignancy

The synuclein family, consisting of alpha-, beta-, and gamma-synuclein, is primarily expressed in neurons. Mutations of alpha- and beta-synuclein have been linked to Parkinson's disease and dementia with Lewy bodies, respectively. Recent studies have shown that synucleins are upregulated in various tumors, including breast, ovarian, meningioma, and melanoma, and high synuclein expression is associated with poor prognosis and drug resistance. We report a novel rearrangement of beta-synuclein in a pediatric T-cell acute lymphoblastic leukemia (T-ALL) case, where beta-synuclein (SNCB) is fused in-frame with ETS variant transcription factor 6 (ETV6), a gene frequently rearranged in acute leukemia including acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia (B-ALL), and T-ALL. An additional case of beta-synuclein rearrangement was identified in a squamous cell carcinoma of the lung through analysis of the public TCGA database. Both rearrangements involve the C-terminal of beta-synuclein. Since beta-synuclein shares extensive amino acid similarities with alpha-synuclein and alpha-synuclein binds to 14-3-3, an important regulator of apoptosis, the rearranged beta-synuclein may contribute to tumorigenesis by deregulating apoptosis. In addition, overexpression of synucleins has been shown to increase cell proliferation, suggesting that the rearranged beta-synuclein may also deregulate the cell cycle.