The outcome of treatment-refractory and/or relapsed pediatric T cell acute lymphoblastic leukemia (T-ALL) is extremely poor1, and the genetic basis for this is not well understood. Here we report comprehensive profiling of 121 cases of pediatric T-ALL using transcriptome and/or targeted capture sequencing, through which we identified new recurrent gene fusions involving SPI1 (STMN1-SPI1 and TCF7-SPI1). Cases positive for fusions involving SPI1 (encoding PU.1), accounting for 3.9% (7/181) of the examined pediatric T-ALL cases, showed a double-negative (DN; CD4−CD8−) or CD8+ single-positive (SP) phenotype and had uniformly poor overall survival. These cases represent a subset of pediatric T-ALL distinguishable from the known T-ALL subsets2 in terms of expression of genes involved in T cell precommitment, establishment of T cell identity, and post-β-selection maturation and with respect to mutational profile. PU.1 fusion proteins retained transcriptional activity and, when constitutively expressed in mouse stem/progenitor cells, induced cell proliferation and resulted in a maturation block. Our findings highlight a unique role of SPI1 fusions in high-risk pediatric T-ALL.
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We gratefully acknowledge the TCGA Consortium and all its members for making their invaluable data publically available. The results published here are in whole or part based upon data generated by the Therapeutically Applicable Research to Generate Effective Treatment (TARGET) initiative managed by the NCI. Information about TARGET can be found at http://ocg.cancer.gov/programs/target. We are also grateful to M. Matsumura, N. Hoshino, K. Yin, F. Saito, Y. Mori, N. Mizota, and M. Nakamura for their excellent technical assistance. We also wish to express our appreciation to M.-J. Park (Gunma Children's Medical Hospital), K. Nomura (Toyama University), H. Kanegane (Tokyo Medical and Dental University), and K. Kato (Ibaraki Children's Hospital) for collecting samples and T. Yasuda, M. Takeyama, J. Mitsui, and S. Tsuji (University of Tokyo) for next-generation sequencing. This work was supported by KAKENHI (17H04224 (J.T.), 26713037 (M.K.), and 15H05909 (S.O.)) from the Japan Society of Promotion of Science; by Japan Agency for Medical Research and Development (AMED) Practical Research for Innovative Cancer Control (16ck0106066h0003 (M. Sanada)) and Project for Cancer Research and Therapeutic Evolution (P-CREATE) (16cm0106509h001 (J.T.)); and by the Friends of Leukemia Research Fund (147100000868 (M. Seki)). This research also used computational resources of the K computer provided by the RIKEN Advanced Institute for Computational Science through the HPCI System Research project (hp140230 (S.M.), hp160219 (S.M.), and hp150232 (S.M.)).
The authors declare no competing financial interests.
Supplementary Figures 1–13. (PDF 12003 kb)
Patient characteristics of 181 T-ALL cases. (XLSX 30 kb)
Fusion genes detected by RNA sequencing in 123 pediatric T-ALL cases. (XLSX 18 kb)
Clinicopathological findings of cases with SPI1 fusion. (XLSX 15 kb)
The number of SPI1 fusion reads and the number of wild-type SPI1 reads that span the exon–exon junction. (XLSX 14 kb)
Bait design for targeted capture sequencing. (XLSX 16 kb)
Mutations detected by targeted capture sequencing. (XLSX 84 kb)
Structural variants detected by targeted capture sequencing. (XLSX 17 kb)
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Seki, M., Kimura, S., Isobe, T. et al. Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia. Nat Genet 49, 1274–1281 (2017). https://doi.org/10.1038/ng.3900
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