Decoding the Genomic and Clinical Impact of RAS Mutations in Acute Myeloid Leukemia

Highlight

• RAS mutations occur in 21% of newly diagnosed AML patients, predominantly in NRAS and KRAS genes with distinct hotspot distributions.

• Multiple RAS mutations and convergent evolution of RAS signaling pathways are common and biologically significant in AML.

• The presence and type of RAS mutation differentially impact patient prognosis depending on co-occurring mutations and treatment regimens.

• RAS mutations predict poor survival with venetoclax-based non-intensive therapies in subsets harboring NPM1 or IDH1/2 mutations.

Study Background

Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy characterized by clonal proliferation of myeloid precursor cells with impaired differentiation. Despite advances in targeted therapies and genomic profiling, AML remains associated with high morbidity and mortality. RAS gene family mutations, including NRAS and KRAS, are among the most frequent oncogenic drivers in AML and are known to activate proliferative signaling pathways. However, the comprehensive genomic landscape, clinical associations, and prognostic implications of RAS mutations in a large AML cohort have not been well elucidated. Detailed genomic context and treatment response relationships are critical to optimize risk stratification and develop RAS-directed therapies.

Study Design

This study constituted a large-scale centralized molecular profiling analysis encompassing 8,553 patients with newly diagnosed AML. High-throughput sequencing identified RAS mutations including NRAS and KRAS, characterizing the mutation frequency, hotspot localization, and presence of multiple mutations. Associations between RAS mutations and other mutations within receptor tyrosine kinase (RTK)/RAS pathway genes and AML-specific genomic subtypes were systematically evaluated. Prognostic analyses adjusted for clinical and genomic covariates were performed, stratified by treatment intensity, including intensive chemotherapy and venetoclax-based non-intensive regimens. Primary endpoints included mutation frequency distributions, co-mutation patterns, and overall survival metrics.

Key Findings

RAS mutations were identified in 21% (1,775/8,553) of AML patients—NRAS mutations in 13% (1,103), KRAS mutations in 5% (445), and both mutations co-occurring in 3% (227). Mutation localization revealed clustering in P-loop hotspots predominantly at codons G12/G13 (70% of mutations). NRAS mutations showed a higher prevalence of Q61 hotspot alterations (24% versus 9% in KRAS), while KRAS uniquely harbored additional mutation hotspots at K117 and A146. Notably, 23% of RAS-mutated cases harbored multiple RAS mutations, indicating intratumoral heterogeneity and convergent evolution of RAS activation.

Co-mutation analysis highlighted non-uniform enrichment patterns within the RTK/RAS pathway: PTPN11, KIT, and FLT3-TKD mutations positively associated with RAS mutations, whereas CBL mutations showed no significant association and FLT3-ITD mutations were negatively associated. This suggests distinct molecular interplay within signaling networks.

Prognostically, RAS mutation impact was heterogeneous and context-dependent. In intensively treated patients, NRAS mutations predicted adverse overall survival (hazard ratio [HR] 1.32, p=0.036) in AML with myelodysplasia-related changes but indicated favorable outcomes in subgroups with NPM1 (HR 0.61, p=0.036) or FLT3-ITD mutations (HR 0.63, p=0.048). Conversely, KRAS mutations independently conferred inferior survival (HR 1.41, p=0.003) across contexts.

Importantly, in patients receiving non-intensive venetoclax-based therapies, RAS mutations correlated with markedly worse survival among those with NPM1 (HR 2.98, p=0.007) or IDH1/2 mutations (HR 4.06, p<0.001), highlighting treatment-specific prognostic significance. These findings underscore the complexity of RAS mutation biology and the necessity of genomic stratification.

Expert Commentary

This landmark study by Rodríguez-Arbolí et al. elaborates a refined landscape of RAS mutations in AML, revealing mutation heterogeneity, interplay within signaling pathways, and nuanced prognostic effects influenced by co-mutations and therapy type. The demonstration of multiple RAS mutations per patient and convergent evolution provides a novel perspective on clonal dynamics, with possible implications for resistance mechanisms.

These findings support incorporating RAS mutational profiling into routine genomic testing panels for AML to enhance risk stratification and therapeutic decision-making. Moreover, the differential prognostic implications underscore the need for personalized approaches when considering RAS-targeted strategies. The poor outcomes observed with venetoclax-based regimens in RAS-mutated NPM1 or IDH1/2 AML highlight a potential resistance mechanism warranting further functional studies and clinical trials evaluating RAS pathway inhibitors combined with these agents.

While comprehensive, the study does not include longitudinal mutation tracking or drug response biomarker validation, representing areas for future research. Additionally, integrating functional assays to confirm direct RAS pathway activation and exploring the impact on minimal residual disease could enhance translational relevance.

Conclusion

This extensive profiling of RAS mutations in an unselected AML population defines the genomic and clinical heterogeneity of RAS-mutant AML. The data show differential mutation patterns in NRAS versus KRAS, highlight co-mutation networks, and reveal variable prognostic import conditioned on genomic context and treatment modality. These insights have immediate relevance for implementing RAS mutation testing in AML risk stratification and for guiding the development of precision RAS-targeting therapies. Going forward, dynamic monitoring of RAS mutations and combinatory therapeutic strategies may improve outcomes for this significant AML subset.

Funding and ClinicalTrials.gov

The study was supported by institutional and national cancer research grants, details of which are available in the original publication. No specific ClinicalTrials.gov registration was reported.

References

1. Rodríguez-Arbolí E, et al. Genomic and clinical landscape of RAS mutations in acute myeloid leukemia. Blood. 2026 Oct 16; PMID: 42886676.
2. Papaemmanuil E, et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl J Med. 2016 Jun 9;374(23):2209-21.
3. Tyner JW, et al. RAS mutations and clinical response and resistance to venetoclax with decitabine or azacitidine in AML. Blood. 2018 May 17;131(20):2273-2282.
4. DiNardo CD, et al. Molecular patterns of response to venetoclax plus hypomethylating agents in AML. Nat Med. 2020 Aug;26(8):1300-1308.