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Recurrent SPI1 (PU.1) fusions in high-risk pediatric T cell acute lymphoblastic leukemia
Masafumi Seki1, Shunsuke Kimura1,2, Tomoya Isobe1
1Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Insights
New gene fusions involving SPI1 (PU.1) were found in high-risk pediatric T cell acute lymphoblastic leukemia (T-ALL). These SPI1 fusions are linked to poor outcomes and represent a distinct T-ALL subset.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Treatment-refractory and relapsed pediatric T cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis.
- The genetic underpinnings of aggressive pediatric T-ALL remain incompletely understood.
Purpose of the Study:
- To comprehensively profile pediatric T-ALL cases to identify novel genetic alterations.
- To investigate the role of newly identified gene fusions in T-ALL pathogenesis and clinical outcomes.
Main Methods:
- Whole transcriptome and targeted capture sequencing were performed on 121 pediatric T-ALL cases.
- Gene fusion analysis identified recurrent fusions involving SPI1 (encoding PU.1).
- Functional studies in mouse stem/progenitor cells assessed the impact of PU.1 fusion proteins.
Main Results:
- Recurrent gene fusions, STMN1-SPI1 and TCF7-SPI1, involving SPI1 were identified in 3.9% of pediatric T-ALL cases.
- SPI1 fusion-positive cases exhibited a double-negative or CD8+ single-positive phenotype and uniformly poor survival.
- These cases represent a distinct T-ALL subset with unique gene expression, mutational profiles, and impaired T cell maturation.
Conclusions:
- SPI1 fusions are a novel driver of high-risk pediatric T-ALL.
- PU.1 fusion proteins promote proliferation and block T cell maturation, contributing to the disease's aggressive nature.
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.
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