Common Driver Mutations in AML: Biological Impact, Clinical Considerations, and Treatment Strategies
Abstract
:1. Introduction to Acute Myeloid Leukemia (AML): Heterogeneity, Molecular Insights, and the Role for Targeted Therapies and Genetic Profiling
2. NPM1 Mutations in AML: Genetic Landscape, Clinical Features, and Therapeutic Innovations
2.1. The Role of NPM1 Mutations in Leukemogenesis Synergistic Genetic Interactions: Impact of Co-Occurring FLT3-ITD Mutations in AML
2.2. Synergistic Genetic Interactions and Prognostic Significance: Impact of Co-Occurring FLT3-ITD Mutations in AML
2.3. Conventional Chemotherapy and Innovations in Targeted Therapy: Current Treatment Approaches for NPM1-Mutated AML, Efficacy of Menin Inhibitors and Combination Strategies
3. FLT3 Mutations in AML: Pathogenesis, Clinical Impact, and Therapeutic Advances
3.1. Prevalence, Mechanism of Action, and Clinical Implications of Constitutive Receptor Activation with FLT3 Mutations
3.2. The Complex Prognostic Landscape of FLT3-ITD Mutations in AML: Clonal Expansion, Relapse Risk, and the Impact of Co-Occurring Mutations
3.3. Targeted FLT3 Inhibitors in AML: Clinical Efficacy and Evolution of Treatment Landscape with Midostaurin, Gilteritinib, Quizartinib, and Emerging Role of Crenolanib
4. TP53 Mutations in AML: Pathogenesis, Clinical Impact, and Emerging Therapeutic Strategies
4.1. Prevalence, Mechanistic Disruption of Cell Function with TP53 Mutations in AML
4.2. Prognostic Implications of TP53 Mutations in AML: Challenges with Treatment Resistance and Poor Clinical Outcomes
4.3. Novel Therapeutic Approaches: Potential of APR-246, MDM2 Inhibitors, and Combination Therapies
5. IDH1/2 Mutations in AML: Pathogenesis, Clinical Impact, and Therapeutic Advances
5.1. Metabolic Disruption and Epigenetic Alterations: The Role of IDH Mutations in Leukemogenesis
5.2. The Controversial Prognostic Impact of IDH1/2 Mutations in AML
5.3. Targeting IDH Mutations in AML: Efficacy of IDH Inhibitors and Combination Therapies
6. Discussion
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Driver Gene Mutation | Biological Consequence | Frequency in AML (%) | Associated Clinical Features | Current FDA Approved Treatments for AML | Emerging Therapies | References |
---|---|---|---|---|---|---|
FLT3-ITD | Constitutive activation of the tyrosine kinase receptor, leading to the potential for uncontrolled malignant proliferation of hematopoietic cells. | 20–30% | intermediate risk (ELN 2022) | TN 1: midostaurin + chemotherapy (NCT00651261) TN: quizartinib + chemotherapy (NCT02039726) R/R: gilteritinib (NCT02421939) | crenolanib (NCT03258931) | [1,3,7,48,50,52,54] |
NPM1 | Impairs the p53 tumor suppressor pathway, reducing apoptosis, and disrupts the nuclear export of ribosomal proteins, allowing myeloid cells to proliferate. | 30% | favorable prognosis in the absence of FLT3-ITD mutations (ELN 2022) | TN: venetoclax + hypomethylating agent (NCT02993523) TN: chemotherapy | R/R: ziftomenib (NCT04067336) R/R: revumenib (NCT04065399) | [3,100,101] |
TP53 | Failure to maintain genomic stability, regulate the cell cycle, and induce apoptosis, which drives leukemogenesis by allowing the survival and proliferation of genetically unstable cells. | 10% | adverse risk (ELN 2022) | TN: venetoclax + hypomethylating agent (NCT02993523) TN: chemotherapy | Combination therapies: | [3,101] |
IDH1/2 | Disruption of cellular differentiation through the inactivation of chromatin by DNA and histone hypermethylation, contributing to leukemogenesis. | IDH1: 5–10% IDH2: 15–20% | Prognostic significance is controversial, although associated with decreased survival. | IDH1: TN: ivosidenib + azacitidine (NCT03173248) R/R: olutasidenib (NCT02719574) IDH2: R/R: enasidenib (NCT02577406) | Combination therapies: ivosidenib with venetoclax ± azacitidine (NCT03471260) | [3,80,82,95,97,98] |
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Nong, T.; Mehra, S.; Taylor, J. Common Driver Mutations in AML: Biological Impact, Clinical Considerations, and Treatment Strategies. Cells 2024, 13, 1392. https://doi.org/10.3390/cells13161392
Nong T, Mehra S, Taylor J. Common Driver Mutations in AML: Biological Impact, Clinical Considerations, and Treatment Strategies. Cells. 2024; 13(16):1392. https://doi.org/10.3390/cells13161392
Chicago/Turabian StyleNong, Tiffany, Shefali Mehra, and Justin Taylor. 2024. "Common Driver Mutations in AML: Biological Impact, Clinical Considerations, and Treatment Strategies" Cells 13, no. 16: 1392. https://doi.org/10.3390/cells13161392