Identification of novel recurrent STAT3-RARA fusions in APL lacking t(15;17)(q22;q12)/PML-RARA. (A,D) May-Grünwald-Giemsa staining showing several abnormal promyelocytes in the diagnostic BM aspirate. (B,E) Interphase fluorescence in situ hybridization (FISH) using the PML-RARA dual-color dual-fusion probes revealed absence of PML-RARA. (C,F) A karyotype performed on the diagnostic BM revealed 45,XY,-Y[6]/46,XY[8] for patient 1 (P1) and 46,XY[20] for patient 2 (P2). (G) Whole-genome sequencing (WGS) analysis results revealed 1 breakpoint in intron 23 or 21 of the STAT3 gene and 2 breakpoints in intron 2 and telomere of exon 9 of the RARA gene. The 3′ region of the RARA gene (from exon 3 to exon 9) was reversed and fused in frame with the 5′ region of the STAT3 gene (from exon 1 to exon 21 or 23) in both patients. (H) Electrophoresis of reverse transcription–polymerase chain reaction (RT-PCR) products from the 2 patients showed distinct STAT3-RARA fusion transcript, and the 2 reciprocal RARA-STAT3 transcripts were also detected. (I) Partial nucleotide sequences surrounding the junctions of the 2 types of STAT3-RARA fusions. The fusion transcript from P1 was a fusion of STAT3 exon 21 and exon 3 of the RARA gene. The fusion transcript from P2 was a fusion of STAT3 exon 23 and exon 3 of RARA gene. (J) Schematic diagram of RARA, STAT3, STAT3-RARA T1, and STAT3-RARA T2 fusion proteins. The breakpoint is indicated by a red line.