Purpose The synuclein family includes a-, b-, g-synuclein and is predominantly expressed in neurons. a- and b-synuclein is mutated in Parkinson's disease and dementia with Lewy bodies. Recent studies found up-regulation of the synucleins in several tumors including breast cancer, ovarian cancer, meningioma, and melanoma, and the high level of synuclein was associated with poor prognosis and drug resistance. We describe here a novel intragenic rearrangement of b-synuclein in pediatric T-cell acute lymphoblastic leukemia (T-ALL). An additional case of b-synuclein rearrangement was found in a squamous cell carcinoma of the lung by searching the public TCGA database. Methods Morphological evaluation and immunohistochemistry were used for diagnostic purposes. Karyotype analysis, targeted RNA NGS, FISH, and RT-PCR were used to identify the fusion transcript. Results A pediatric T-ALL carried a translocation of chromosomes 5 and 12, resulting in an in-frame fusion between the b-synuclein (SNCB) and the ETS variant transcription factor 6 (ETV6), a gene frequently rearranged in acute myeloid leukemia (AML), B-ALL, and T-ALL. Another SNCB rearrangement involved low-density lipoprotein receptor class A domain containing 3 (LDLRAD3) in a lung carcinoma. Both fusions retained the c-terminal of b-synuclein, a region important for protein interaction. Conclusion We describe the first cases of b-synuclein rearrangement in tumors. Since b-synuclein shares extensive similarity in amino acid sequences with a-synuclein and the a-synuclein binds to 14-3-3, an important regulator of apoptosis, we suspect that the rearranged b-synuclein likely contributes to tumorigenesis by deregulating apoptosis. In addition, the rearranged b-synuclein could deregulate the cell cycle, because overexpression of b-synuclein leads to increased cell proliferation.

Juvenile myelomonocytic leukemia (JMML) is an aggressive clonal hematopoietic disorder of infancy and early childhood. About 15% of these patients have CBL mutation, which is usually a germline mutation with a high incidence of CBL syndrome. Conventional chemotherapy would be little benefit to these children, but epigenetic therapy with the DNA-hypomethylating agents can make a great difference in disease control. Here we report two infants diagnosed as JMML with CBL mutation. One case was treated with 6-mercaptopurine intermittently, but she was often hospitalized for pneumonia since the disease was not well controlled. The other one was treated with decitabine. He achieved clinical complete remission (CR) after three cycles of decitabine (20mg/m2/d×5 days, repeated every 4 weeks). Unfortunately, the patient's symptoms were recurrent two months later. Thus, JMML patient with CBL mutation has a good clinical response to decitabine, while how and how long it could be used remain to be further explored.

The synuclein family, consisting of α-, β-, and γ-synuclein, is primarily expressed in neurons. Mutations of α- and β-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 β-synuclein in a pediatric T-cell acute lymphoblastic leukemia (T-ALL) case, where β-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 β-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 β-synuclein. Since β-synuclein shares extensive amino acid similarities with α-synuclein and α-synuclein binds to 14-3-3, an important regulator of apoptosis, the rearranged β-synuclein may contribute to tumorigenesis by deregulating apoptosis. In addition, overexpression of synucleins has been shown to increase cell proliferation, suggesting that the rearranged β-synuclein may also deregulate the cell cycle.