PRDM16::SKI is a predictor of aberrant expression of the short variant of PRDM16 in pediatric acute myeloid leukemia

The RNA-sequencing data from the Japanese Children’s Cancer Group (JCCG)’s AML-05 study was re-analyzed to clarify the mechanisms related to high PRDM16 expressions, which is independently associated with adverse outcomes. Results showed that 19 of 139 patients presented with out-of-frame PRDM16::SKI fusions. Thus, the gene expression levels of PRDM16::SKI in 369 and 329 patients from the AML-05 and AML-12 studies, respectively, were measured. In total, 119 (32%) of 369 patients in the AML-05 study and 58 (18%) of 329 patients in the AML-12 study presented with an aberrant expression of PRDM16::SKI. This fusion was a 48-base-pair product that immediately formed a stop codon on the SKI side. The introduction of this product in mice did not cause AML. Intriguingly, none of the patients presented with SKI::PRDM16, which is reciprocal. Moreover, partner fusion genes were not detected in front of truncated PRDM16, indicating that a short form of PRDM16, which lacked exon 1, existed by itself. Patients with high PRDM16::SKI expression had significantly worse overall survival and event-free survival than those with a low PRDM16 expression. The cleavage between exons 1 and 2 of PRDM16 induces aberrant PRDM16 expression, and a strong associations was observed between PRDM16::SKI and PRDM16 expression.