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Nat Genet. 2017 Aug;49(8):1274-1281. doi: 10.1038/ng.3900. Epub 2017 Jul 3.

Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia.

Author information

1
Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
2
Department of Pediatrics, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan.
3
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
4
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
5
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.
6
Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
7
Division of Systems Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
8
Laboratory of Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
9
Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.
10
Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.
11
Division of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
12
Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan.
13
Department of Pediatrics, Sapporo Hokuyu Hospital, Sapporo, Japan.
14
Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan.
15
Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.
16
Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
17
Department of Hematology and Oncology, Miyagi Children's Hospital, Sendai, Japan.
18
Gunma Children's Medical Center, Shibukawa, Japan.
19
Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan.
20
Department of Pediatrics, Toho University, Tokyo, Japan.
21
Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
22
Department of Cellular Signaling, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Abstract

The outcome of treatment-refractory and/or relapsed pediatric T cell acute lymphoblastic leukemia (T-ALL) is extremely poor, 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 subsets 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.

PMID:
28671687
DOI:
10.1038/ng.3900
[Indexed for MEDLINE]

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