Clonal architecture of FLT3-ITD and acquired 13q uniparental disomy define prognostic heterogeneity and therapeutic vulnerabilities in acute myeloid leukemia.

Acute myeloid leukemia (AML) is characterized by the sequential accumulation of genetic mutations in hematopoietic stem/progenitor cells (HSPCs). The FLT3-ITD mutation, occurring in 20-30 % of AML cases, typically emerges as a late event. Despite its established association with adverse prognosis, significant outcome heterogeneity persists in FLT3-ITD AML. The clonal origin of FLT3-ITD may serve as a critical determinant of phenotypic and prognostic variability, though the underlying mechanisms remain poorly understood. This study enrolled 149 FLT3-ITD AML patients. Genomic and transcriptomic profiling defined four prognostic origin subtypes (DNMT3A/NPM1-mutation, IDH/NPM1-mutation, transcription factor [TF]-related lesion and other genetic lesion origin). Within the high risk DNMT3A/NPM1-origin subgroup, stratification by differentiation state showed hematopoietic stem cell arrest conferred an inferior event-free survival compared with arrest at the monocyte stage. Analysis of refractory/relapsed (R/R) cases revealed the prevalence of baseline 13q uniparental dismoy (UPD) in DNMT3A/NPM1-origin subgroup. All DNMT3A/NPM1-origin patients acquired 13q UPD at the R/R stage, arising from either expansion of pre-existing UPD subclones or de novo UPD acquisition under therapeutic pressure. Single-cell analysis further revealed aberrant activation of the DNA homologous recombination repair in DNMT3A/NPM1-origin patient blasts and triple-mutant mouse HSPCs. In conclusion, FLT3-ITD clonal origin demonstrated significant impact on the outcome of AML. Acquired 13q UPD drives clonal evolution and disease progression in the DNMT3A/NPM1-origin subgroup, highlighting its potential as a therapeutic target.