A line in shifting sand: Can we define and target TP53 mutated MDS?

Sarah Skuli; Andrew Matthews; Martin Carroll; Catherine Lai

doi:10.1053/j.seminhematol.2024.10.009

A line in shifting sand: Can we define and target TP53 mutated MDS?

Semin Hematol. 2024 Nov 6:S0037-1963(24)00126-4. doi: 10.1053/j.seminhematol.2024.10.009. Online ahead of print.

Authors

Sarah Skuli¹, Andrew Matthews¹, Martin Carroll¹, Catherine Lai²

Affiliations

¹ Division of Hematology and Oncology, Department of Medicine, The University of Pennsylvania, Philadelphia, PA.
² Division of Hematology and Oncology, Department of Medicine, The University of Pennsylvania, Philadelphia, PA. Electronic address: catherine.lai@pennmedicine.upenn.edu.

PMID: 39542753
DOI: 10.1053/j.seminhematol.2024.10.009

Abstract

Mutations in the tumor suppressor protein, TP53, lead to dismal outcomes in myeloid malignancies, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Recent pathological reclassifications have integrated TP53 mutated MDS and AML under a unified category of TP53 mutated myeloid neoplasms, which allows for more flexibility in treatment approaches. Therapeutic strategies have predominantly mirrored those for AML, with allogeneic stem cell transplantation emerging as critical for long-term disease control. The question remains whether there are physiological distinctions within TP53 mutated myeloid neoplasms that will significantly impact prognosis and therapeutic considerations. This review explores the unique aspects of classically defined "TP53 mutated MDS", focusing on its distinct biological characteristics and outcomes. Our current understanding is that TP53 mutated MDS and AML are globally quite similar, but as a group have unique features compared to TP53 wildtype (WT) disease. Optimizing immunotherapy and targeting vulnerabilities due to co-mutations and/or chromosome abnormalities should be the focus of future research.

Keywords: AML; Biology; MDS; TP53; Treatment.