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

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


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.

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Female
  • Gene Expression Profiling
  • Gene Fusion*
  • Genetic Predisposition to Disease
  • Humans
  • Infant
  • Male
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / immunology
  • Proto-Oncogene Proteins / genetics*
  • Survival Analysis
  • T-Lymphocyte Subsets
  • Trans-Activators / genetics*


  • Proto-Oncogene Proteins
  • Trans-Activators
  • proto-oncogene protein Spi-1