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Modelling KRAS Mutations in KMT2A-MLLT3 AML Promotes Leukemic Progression and Transcriptomic Remodeling

ABSTRACT: KRAS mutations are frequently detected in acute myeloid leukemia (AML) with KMT2A-MLLT3 (KM3) rearrangements, yet their biological impact remains poorly understood. Using a humanized in vivo KM3 AML model, we introduced KRAS G13D or G12C point mutations via CRISPR-Cas9 in CD34⁺ cord blood cells to mimic subclonal events observed in patients. We found that KRAS mutations significantly accelerated leukemia onset and increased leukemic stem cell (LSC) frequency by over 20-fold, without altering the surface phenotype. Transcriptomic profiling revealed extensive gene expression reprogramming, including upregulation of stemness- and quiescence-associated genes such as IKZF2 and ALOX15, and activation of inflammatory and NF-κB signaling pathways. Single-cell RNA sequencing uncovered a distinct population with a conventional type 1 dendritic cell (cDC1)-like transcriptional profile, emerging exclusively in KRAS-mutated leukemias and expressing key LSC regulators. This suggests that KRAS mutations not only enhance aggressiveness but also drive cellular heterogeneity within the leukemic clone. Importantly, clinical data from the HARMONY cohort confirmed that KM3 patients harboring KRAS mutations exhibit significantly reduced overall survival, a trend consistent across age groups and fusion partners. Together, our findings demonstrate that KRAS mutations exacerbate leukemogenesis in KM3 AML by promoting stemness, transcriptional rewiring, and subclonal diversification. This study provides both mechanistic insight and a clinically relevant model supporting the development of KRAS-targeted therapies in this aggressive AML subset.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300354 | GEO | 2026/06/19

REPOSITORIES: GEO

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