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TP53-mutated myeloid neoplasms including acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are notoriously treatment resistant with uniformly poor outcomes. TP53 status is an important prognostic indicator and early knowledge of the TP53 mutation/allelic state may assist in appropriate management including clinical trial enrollment for eligible patients. Thus far, no therapy has shown to demonstrate durable response or incremental survival benefit in TP53-mutated AML or MDS. Therefore, there is an urgent need for innovative therapies to improve the outcomes in this notoriously recalcitrant genomic subset. In this review, we dissect the biology, classification, prognosis, current treatment landscape, and the early phase evaluation of investigational agents in TP53-mutated AML and MDS.
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http://dx.doi.org/10.1159/000534566 | DOI Listing |
Front Oncol
August 2025
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia.
mutations drive oncogenesis and therapeutic resistance in myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML), impairing p53-regulated functions such as apoptosis, immune surveillance, and genomic stability, leading to immune evasion and metabolic reprogramming. The tumor microenvironment in -mutated MDS and AML fosters leukemic progression through cytokine dysregulation, altered metabolism, and immune suppression. Current therapies, including chemotherapy and hypomethylating agents, offer limited efficacy, resulting in poor overall survival rates for these high-risk patients.
View Article and Find Full Text PDFCancer Lett
September 2025
Research Institute of Pharmaceutical Sciences & Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea. Electronic address:
Tumor protein 53 (TP53)-mutated acute myeloid leukemia (AML) is characterized by poor outcomes and the quick development of treatment resistance. Here, we report that simultaneous inhibition of cyclin-dependent kinases (CDKs) and histone deacetylases (HDACs) with dinaciclib and CAY10603, respectively, eliminates the therapeutic response gap between TP53-mutant and TP53 wild-type AML. Biochemical profiling showed that CAY10603 is not only HDAC6-selective but also exhibits pan-HDAC activity similar to suberoylanilide hydroxamic acid, enabling dual targeting of transcriptional and cell cycle pathways.
View Article and Find Full Text PDFUnlabelled: Patients with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) with high-risk features including mutations and deletions have poor outcomes due to lack of effective therapies. The atypical chemokine surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is overexpressed in MDS and secondary AML (sAML) compared to healthy hematopoietic cells and we recently found that -mutated MDS/AML and AML with erythroid features express the highest levels of this receptor across MDS/AML subtypes. To illustrate the therapeutic potential of CCRL2 as a therapeutic target, we developed an anti-CCRL2 antibody-drug conjugate (ADC) by conjugating an anti-CCRL2 antibody with the cytotoxic drug pyrrolobenzodiazepine (PBD), which causes DNA double-strand breaks leading to cancer cell death.
View Article and Find Full Text PDFHum Genomics
August 2025
Department of Hematology, Peking University First Hospital, Beijing, China.
Unlabelled: While variant is an adverse prognosis factor in myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), current clinical prognosis and variation feature analysis of alterations remain limited. We evaluated 333 MDS/AML patients with mutations, single nucleotide polymorphisms (SNPs), and wild-type to characterize clinical features and identify prognostic factors using next-generation sequencing (NGS) data. Interpretation requires caution due to sample size limitations, particularly in subgroup analyses.
View Article and Find Full Text PDFHaematologica
August 2025
Division of Hematologic Malignancies and Bone Marrow Transplantation, Department of Medical Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Patients with myeloid neoplasms with loss-of-function TP53 mutations and erythroid differentiation have poor outcomes, and a better understanding of disease biology is required. Upregulation of interferon-γ (IFN-γ) signaling has been associated with acute myeloid leukemia (AML) progression, selection of TP53 mutated clones and chemotherapy resistance, but its drivers remain unclear. In this study, we found that the surface receptor C-C motif chemokine receptor-like 2 (CCRL2) is overexpressed in AML with erythroid differentiation and TP53 mutations compared to other AML subtypes and healthy hematopoietic cells.
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