Work

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

Year: 2025

Type: article

Abstract: 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.

Source: Neoplasia

DOI: 10.1016/j.neo.2025.101264