Recurrent SPI1 fusions in pediatric T-cell acute lymphoblastic leukemia: novel mutations with poor prognosis

Abstract

The outcome of treatment-refractory and/or relapsed pediatric T-cell acute lymphoblastic leukemia (T-ALL) is extremely poor, and the genetic basis of these cases remains poorly understood. Here, we report comprehensive profiling of 121 cases of pediatric T-ALL using RNA sequencing 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), which accounted for 3.9% (7/181) of the total examined pediatric T-ALL cases, 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 pre-commitment, establishment of T cell identity, and post-β-selection maturation with respect to mutational profile. PU.1 fusion proteins retained transcriptional activity and induced cell proliferation on constitutive expression in mouse stem/progenitor cells, resulting in a maturation block. Our findings highlight the unique role of SPI1 fusions in high-risk pediatric T-ALL.