Characterization of fusion transcripts in AML without recurrent genetic abnormalities unravels new putative fusion genes

• Whole transcriptome sequencing identifies fusion transcripts with diagnostic and therapeutic significance in AML without recurrent genetic abnormalities.

• Thorough examination of novel fusion transcripts unravels putative driver fusion genes with therapeutic potential and impact on disease monitoring.

In the last, few years, whole transcriptome sequencing has shown a high number of low-frequency fusion transcripts (FT) involved in acute myeloid leukemia (AML) pathogenesis. Most of them are not identifiable through conventional diagnostic techniques. In this research, using RNA sequencing, we have investigated FT in 109 cases of AML without recurrent genetic abnormalities (as defined by the 4th edition of the World Health Organization Classification of Haematolymphoid Tumours). We identified and validated six well-known AML-causing FT (Tier-1), nine FT in which recurrently affected genes in AML were involved (Tier-2) and four Tier-3 FT, along with other FT found in healthy tissue databases (Tier-4). We highlighted two previously unknown FT (ARHGAP11A::NUTM1 and RAP1B::GPC3) that constitute putative driver fusion genes in AML after performing a thorough analysis of their intrinsic properties, expression pattern and clinical data correlation. Altogether, 15 patients from our cohort (14%) presented at least one validated FT, half of which had diagnostic and/or therapeutic implications. Furthermore, we were able to monitor eight FT during disease evolution, finding a good correlation with tumor burden. Nevertheless, the significance of many FT remains unknown, which makes it necessary to enlarge curated FT databases to implement whole transcriptome sequencing inclinical practice.