2.1 – Fusion Cytogenetics
As part of our recently completed discovery efforts in childhood AML (TpAML), we interrogated the transcriptome of 1068 children and young adults treated on the COG Phase 3 clinical trial, AAML1031, via RNA sequencing. From these efforts, we identified cryptic and karyotypically identified fusions involving the ALK gene in 4 patients. The ALK fusions included SPTBN1-ALK (n=3) or RANBP2-ALK (n=1) (Fig. 1A)6. Notably, all four ALKfuscases occurred exclusively in patients with Mono7, constituting 14.3% of patients with Mono7 (4 of 28); ALK fusions were not detected in the remaining 1064 patients (Fig. 1B). In all four cases the entire kinase domain of the ALK gene was retained. Importantly, overexpression of the ALK gene was only identified in the four ALKfus positive cases with a mean TPM expression of 11.76 versus 0 for ALKfus negative patients (Fig. 1B; p<0.0001), suggesting that ALKfusupregulates ALK expression. The single RANBP2-ALK case additionally harbored chromosome inversion 2, while only one of theSPTBN1-ALK cases was noted to harbor inversion 2; no other cytomolecular aberration was observed in any ALKfuscases (TABLE 1).