CRISPR-Cas9 in Myelodysplastic Syndromes: The Potential of Editing DNMT3A, TET2, ASXL1, TP53, and SF3B1 to Prevent Disease Progression—A Literature Review
DOI:
https://doi.org/10.5281/zenodo.22799703Keywords:
CRISPR-Cas9; myelodysplastic syndromes; genome editing; clonal hematopoiesis; disease progressionAbstract
Myelodysplastic syndromes are clonal hematopoietic stem cell neoplasms characterized by ineffective hematopoiesis and a variable risk of transformation to acute myeloid leukemia. This study examines the potential of CRISPR-Cas9 editing of DNMT3A, TET2, ASXL1, TP53, and SF3B1 to prevent disease progression. A narrative and critical literature review was conducted using electronic searches and reference tracking, with sources consulted in September 2026. The synthesis distinguishes prognostic associations, experimental modeling, functional correction, and clinical evidence. ASXL1 correction has provided proof of concept in leukemic cells and xenografts; TET2 restoration supports the possibility of reversing preleukemic phenotypes, although some of this evidence does not involve CRISPR-Cas9. DNMT3A studies show that dependence on a mutation may differ between disease initiation and maintenance. For TP53, allelic complexity and the response to genomic damage pose substantial obstacles. For SF3B1, co-mutations and the need to preserve physiological RNA processing limit indiscriminate inactivation strategies. The selected literature does not demonstrate clinical prevention of myelodysplastic syndrome progression through correction of these five genes. Clonal heterogeneity, delivery to stem cells, persistence of additional alterations, and genomic safety remain challenges. CRISPR-Cas9 is an established tool for causal investigation and a promising therapeutic platform, but its preventive application in this setting remains experimental. Clinical immunology contributes to understanding the interplay between inflammation, clonal selection, and hematopoietic reconstitution, and to defining outcomes beyond a reduction in variant frequency alone
References
1. Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703-1719. doi:10.1038/s41375-022-01613-1.
2. Bernard E, Tuechler H, Greenberg PL, Hasserjian RP, Arango Ossa JE, Nannya Y, et al. Molecular International Prognostic Scoring System for Myelodysplastic Syndromes. NEJM Evid. 2022;1(7):EVIDoa2200008. doi:10.1056/evidoa2200008.
3. DiPersio JF, Koehne G, Shah NN, Bernard L, Suh HC, Koura D, et al. CRISPR−Cas9 CD33-deleted allogeneic hematopoietic cell transplantation with gemtuzumab ozogamicin maintenance in AML: a phase 1/2 trial. Nat Med. 2026;32(5):1763-1772. doi:10.1038/s41591-026-04362-1.
4. Köhnke T, Karigane D, Hilgart E, Fan AC, Kayamori K, Miyauchi M, et al. DNMT3A R882H Is Not Required for Disease Maintenance in Primary Human AML but Is Associated with Increased Leukemia Stem Cell Frequency. Cancer Discov. 2026;16(3):592-610. doi:10.1158/2159-8290.cd-24-1604.
5. Cimmino L, Dolgalev I, Wang Y, Yoshimi A, Martin GH, Wang J, et al. Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression. Cell. 2017;170(6):1079-1095.e20. doi:10.1016/j.cell.2017.07.032.
6. Bernard E, Nannya Y, Hasserjian RP, Devlin SM, Tuechler H, Medina-Martinez JS, et al. Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes. Nat Med. 2020;26(10):1549-1556. doi:10.1038/s41591-020-1008-z.
7. Tothova Z, Krill-Burger JM, Popova KD, Landers CC, Sievers QL, Yudovich D, et al. Multiplex CRISPR/Cas9-Based Genome Editing in Human Hematopoietic Stem Cells Models Clonal Hematopoiesis and Myeloid Neoplasia. Cell Stem Cell. 2017;21(4):547-555.e8. doi:10.1016/j.stem.2017.07.015.
8. Sarchi M, Clough CA, Gallì A, Picone C, Ferrari B, Crosse EI, et al. Distinct routes of clonal progression in SF3B1-mutant myelodysplastic syndromes. Blood Adv. 2025;9(12):3044-3055. doi:10.1182/bloodadvances.2024014965.
9. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity. Science. 2012;337(6096):816-821. doi:10.1126/science.1225829.
10. Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature. 2016;533(7603):420-424. doi:10.1038/nature17946.
11. Anzalone AV, Randolph PB, Davis JR, Sousa AA, Koblan LW, Levy JM, et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature. 2019;576(7785):149-157. doi:10.1038/s41586-019-1711-4.
12. Wang T, Pine AR, Kotini AG, Yuan H, Zamparo L, Starczynowski DT, et al. Sequential CRISPR gene editing in human iPSCs charts the clonal evolution of myeloid leukemia and identifies early disease targets. Cell Stem Cell. 2021;28(6):1074-1089.e7. doi:10.1016/j.stem.2021.01.011.
13. Silver AJ, Brown DJ, Olmstead SD, Watke JM, Gorska AE, Tanner L, et al. Interallelic gene conversion of leukemia-associated single nucleotide variants. Gene. 2025;958:149493. doi:10.1016/j.gene.2025.149493.
14. Valletta S, Dolatshad H, Bartenstein M, Yip BH, Bello E, Gordon S, et al. ASXL1 mutation correction by CRISPR/Cas9 restores gene function in leukemia cells and increases survival in mouse xenografts. Oncotarget. 2015;6(42):44061-44071. doi:10.18632/oncotarget.6392.
15. Thier J, Hofmann S, Kirchhof KM, Todisco G, Mortera-Blanco T, Lilienthal I, et al. SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms. Leukemia. 2025;39(11):2801-2811. doi:10.1038/s41375-025-02740-1.
16. Cai Z, Kotzin JJ, Ramdas B, Chen S, Nelanuthala S, Palam LR, et al. Inhibition of Inflammatory Signaling in Tet2 Mutant Preleukemic Cells Mitigates Stress-Induced Abnormalities and Clonal Hematopoiesis. Cell Stem Cell. 2018;23(6):833-849.e5. doi:10.1016/j.stem.2018.10.013.
17. Haapaniemi E, Botla S, Persson J, Schmierer B, Taipale J. CRISPR–Cas9 genome editing induces a p53-mediated DNA damage response. Nat Med. 2018;24(7):927-930. doi:10.1038/s41591-018-0049-z.
18. Kosicki M, Tomberg K, Bradley A. Repair of double-strand breaks induced by CRISPR–Cas9 leads to large deletions and complex rearrangements. Nat Biotechnol. 2018;36(8):765-771. doi:10.1038/nbt.4192.
19. Everette KA, Newby GA, Levine RM, Mayberry K, Jang Y, Mayuranathan T, et al. Ex vivo prime editing of patient haematopoietic stem cells rescues sickle-cell disease phenotypes after engraftment in mice. Nat Biomed Eng. 2023;7(5):616-628. doi:10.1038/s41551-023-01026-0.
20. Frangoul H, Locatelli F, Sharma A, Bhatia M, Mapara M, Molinari L, et al. Exagamglogene Autotemcel for Severe Sickle Cell Disease. N Engl J Med. 2024;390(18):1649-1662. doi:10.1056/nejmoa2309676.
21. Fiumara M, Ferrari S, Omer-Javed A, Beretta S, Albano L, Canarutto D, et al. Genotoxic effects of base and prime editing in human hematopoietic stem cells. Nat Biotechnol. 2024;42(6):877-891. doi:10.1038/s41587-023-01915-4.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Thauann Lima Silva Rufino
This work is licensed under a Creative Commons Attribution 4.0 International License.
