CRISPR-Cas9 in Myelodysplastic Syndromes: The Potential of Editing DNMT3A, TET2, ASXL1, TP53, and SF3B1 to Prevent Disease Progression—A Literature Review

Abstract

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.