ISSN 2997-1036
International Journal of Hematology | Vol. 13, No. 1, January 2022 | pp. 1–8
DOI: 10.46882/2022/IJH/000143
Review Article
Title: Structural architecture and target chemical inhibition of the TP53 pathways in therapy-related acute myeloid leukemia
Names of Authors: M. A. Bello¹, O. R. Eze²
Authors’ Affiliations: ¹Department of Haematology, Aminu Kano Teaching Hospital, Kano, Nigeria; ²Department of Pathology, University of Benin, Benin City, Nigeria
Abstract: Mutations within the tumor suppressor TP53 gene occur frequently in therapy-related acute myeloid leukemia, correlating with complex karyotypes and severe resistance to standard DNA-damaging cytotoxic chemotherapies. This comprehensive review synthesizes the molecular structural architecture of TP53 disruptions, contrasting missense alterations within the DNA-binding domain with complete multi-allelic deletions. These structural modifications impair p53-mediated transcriptional activation of pro-apoptotic elements, allowing highly abnormal myeloid clones to survive and multiply. Traditional anthracycline and cytarabine induction regimens fail to achieve durable remission in over 80% of TP53-mutated cases. Evolving treatment frameworks emphasize small-molecule targeted therapies, including eprenetapopt (APR-246), which acts by restoring standard wild-type confirmation to mutated p53 proteins, and selective MDM2 inhibitors for TP53 wild-type overexpressing variants. Combining these confirmation restoration agents with low-intensity hypomethylating backbones represents a promising frontier for bypassing standard chemoresistance. This review outlines a clear molecular risk assessment checklist, variant allele fraction tracking systems, and clinical management pathways designed to optimize clonal clearance in therapy-related leukemias.
Keywords: Acute myeloid leukemia, TP53 mutation, eprenetapopt, chemoresistance, tumor suppressor pathways
Manuscript Timeline: Received: October 12, 2021; Revised: November 22, 2021; Accepted: December 10, 2021; Published: January 16, 2022