Identification of cryptic KMT2A-PTD and other novel fusion genes by transcriptome sequencing alters molecular risk...

Acute myeloid leukaemia with normal karyotype (AML-NK) is a cytogenetically cryptic yet heterogeneous clinical subgroup that lacks structural chromosomal abnormalities. Although classified as an intermediate-risk group, AML-NK exhibits variability in patient outcomes, underscoring the need for refined molecular stratification. In this study, high-throughput deep sequencing was performed on 51 AML-NK patients, with a comprehensive analysis of a Southeast Asian cohort to identify cryptic and novel fusion genes potentially implicated in disease pathogenesis and prognosis. Two pipelines (Arriba and STAR-fusion) were utilised in this study, which identified 68 findings involving 27 fusion genes, of which approximately 70% (n = 19/27) were novel. The majority (85%) were intrachromosomal fusion events, and 26% involved non-coding RNAs. The most recurrent and novel fusions were LATS2::SAP18 (17.6%) and HOXA3::HOXA9 (15.7%). In addition, known prognostic fusion genes, KMT2A-PTD, NUP98::NSD1, and NPM1::MLF1, were detected. The integration of these prognostic fusion genes into the ELN 2022 criteria reclassified 73% (n = 8/11) of intermediate-risk patients as poor-risk. Notably, the presence of KMT2A-PTD and/or LATS2::SAP18 was associated with reduced overall survival (p = 0.039, Log-Rank), although this significance was not retained in multivariate analysis. This study's findings revealed the complexity of the AML-NK transcriptome, highlighting the utility of RNA sequencing for prognostic risk assessment and therapeutic strategy development. KEY MESSAGE: RNA-seq uncovered 27 fusion genes in AML-NK, 70% of which were novel. Recurrent LATS2::SAP18 and HOXA3::HOXA9 fusions were identified. Fusion-based ELN 2022 reclassified most intermediate-risk patients. RNA-seq enhances prognostic assessment in AML-NK.