Abstract
NAB2–STAT6 gene fusions occur in the vast majority of solitary fibrous tumors.
Major finding: NAB2–STAT6 gene fusions occur in the vast majority of solitary fibrous tumors.
Mechanism: The activation domain of STAT6 converts NAB2 from an EGR repressor to an activator.
Impact: Inhibition of NAB2–STAT6 targets may be an effective therapeutic strategy in solitary fibrous tumors.
Solitary fibrous tumors (SFT) are rare soft-tissue sarcomas with no known recurrent genetic lesions. Using paired-end RNA sequencing and PCR screening, Robinson and colleagues found recurrent fusion transcripts in SFTs caused by inversions at chromosome 12q13 involving NAB2 and STAT6, adjacent genes normally transcribed in opposite directions. In-frame NAB2–STAT6 fusion transcripts were identified in 51 of 51 SFTs tested regardless of the site of origin or whether the tumor was benign or malignant. Every NAB2–STAT6 fusion variant encoded a protein product that combined the EGR-binding domain of NAB2, a repressor of early growth response (EGR) zinc-finger transcription factors that regulate differentiation and proliferation, with the transactivation domain of STAT6, a transcription factor that mediates cytokine signaling. NAB2–STAT6 increased normal cell proliferation and induced EGR1-dependent expression but did not lead to constitutive STAT6 phosphorylation or activation of a STAT6-dependent reporter. The NAB2–STAT6 fusion protein also specifically bound EGR1 target gene promoters, and known EGR target genes showed outlier expression levels in SFTs compared with other tumor types. Consistent with these results, Chmielecki and colleagues analyzed SFT whole-exome sequencing data and found NAB2–STAT6 fusion transcripts in a total of 29 of 53 (55%) SFTs but not in other tumor types, though this observation likely was an underestimate of the true frequency because intronic fusions are undetectable by whole-exome sequencing. Collectively, these findings suggest that conversion of NAB2 from an EGR repressor to an EGR activator by fusion with STAT6 is a driving event in the initiation of SFT and that inhibition of downstream EGR targets should be considered for treatment of these rare sarcomas.
