bims-p53act 2025-12-14 papers

J Cell Biochem. 2025 Dec;126(12): e70076

Integrative Multi-Omics Analysis Unveils the Molecular Mechanisms by Which TP53 Mutation Influence Early Decitabine Resistance in Myelodysplastic Syndrome.

Wei Chen, Xiaojing Ge, Hailing Xu, Tong Yang, Xiuying Wu, Jinting An, Yuye Ren, Lan Zhang.

The myelodysplastic syndrome (MDS) is group of clonal hematopoietic stem cell disorders typified by peripheral cytopenia, dysplastic hematopoietic progenitors, a hypercellular or hypocellular bone marrow, and a high risk of conversion to acute myeloid leukemia. TP53 is a tumor suppressor gene that plays an important role in tumor suppression. Decitabine (DAC) monotherapy has been shown to improve the response rates in TP53-mutated MDS, while the molecular mechanisms of clinical responses are unclear. This study aimed to initially evaluate the TP53 gene locus mutation and the regulation mechanism of DAC on gene expression in AML-MDS cell lines. We detected the mutation of TP53 gene locus in three myeloid tumor cell lines, SKM-1 (mutTP53), M-07e (wtTP53) and HL60 (nullTP53). Then, we performed transcriptomic and proteomic and methylation data in M-07e (wtTP53) and SKM-1 (mutTP53) cells and screened out LGALS1, which is a poor prognostic indicator, as the potential target of TP53 by comparing analysis. We uncovered 31 potential key genes showing differential early responses to DAC treatment in TP53-mutant versus wild-type cells, which may be associated with resistance development. This study revealed the potential molecular mechanisms of TP53 gene locus mutation in DAC-treated MDS.

Keywords: DNA methylation; TP53 mutation; cell transcriptome; decitabine; myelodysplastic syndrome; proteome

DOI: https://doi.org/10.1002/jcb.70076

Med Oncol. 2025 Dec 12. 43(1): 54

A new approach for elimination of apoptotic resistance caused by MDM2/MDMX amplification in chronic lymphocytic leukemia: combination of ALRN-6924 and radiofrequency exposure.

Berrak Kurt, Handan Kayhan, Elçin Özgür Büyükatalay, Görkem Kısmalı.

Chronic lymphocytic leukemia (CLL) is characterized by mature B lymphocyte accumulation and frequent MDM2/MDMX overexpression, leading to p53 inactivation and apoptotic resistance. ALRN-6924, a stapled peptide dual inhibitor, targets MDM2/MDMX to restore p53 function. This study evaluated ALRN-6924 efficacy alone and combined with radiofrequency (RF) exposure in CLL cell lines. Molecular docking assessed ALRN-6924-MDM2 binding affinity. Cytotoxic and apoptotic effects were evaluated using XTT assays and flow cytometry in HG-3 (wild-type p53) and MEC-1 (mutant p53) cell lines. Treatments included ALRN-6924 monotherapy and combination with 900 MHz RF exposure (120 mW/cm2). MDM2, MDMX, BCL-2, and p53 protein levels were quantified by ELISA. Molecular docking revealed strong ALRN-6924-MDM2 binding (energy: - 9.30 kcal/mol, Ki: 163.9 nM). ALRN-6924 demonstrated potent cytotoxicity in HG-3 cells (IC50: 7.54 μM at 24 h, 5.88 μM at 48 h) versus resistance in MEC-1 cells (IC50: ~ 36 μM). In HG-3 cells, ALRN-6924 significantly induced apoptosis and necroptosis, reduced MDM2/MDMX expression, and enhanced p53 levels. RF combination therapy showed synergistic effects, further improving efficacy compared to monotherapy. BCL-2 expression was significantly reduced in the combination group. ALRN-6924 demonstrates promising therapeutic potential in wild-type p53 CLL cells, with enhanced efficacy when combined with RF exposure. The compound effectively disrupts the MDM2/MDMX-p53 axis, restoring p53 function and inducing programmed cell death. In mutant p53 cells, combination therapy may provide partial benefits. These findings support ALRN-6924 clinical development as targeted therapy for p53-functional CLL, particularly in combination strategies.

Keywords: ALRN-6924; Apoptosis; Chronic lymphocytic leukemia; MDM2; MDMX; Radiofrequency exposure; Targeted therapy; p53 tumor suppressor

DOI: https://doi.org/10.1007/s12032-025-03169-3

J Clin Med. 2025 Nov 29. pii: 8480. [Epub ahead of print]14(23):

TP53 Mutations in Mantle Cell Lymphoma: From Backup to Game Changer.

Maria Elena Carazzolo, Alessia Moioli, Carlo Visco.

Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) whose clinical course is largely shaped by molecular and biological features. Among the most impactful prognostic markers, TP53 mutations have emerged as critical determinants of treatment resistance since their first identification in MCL in 1996. Regardless of the detection method, TP53 mutations have been consistently associated with primary refractoriness to chemoimmunotherapy and significantly reduced overall survival. In this perspective, we explored recent advances in applying integrated-omics approaches to assess TP53 status. Despite its prognostic value, routine testing for TP53 at diagnosis remains uncommon, hindered by the lack of standardized protocols and costs for Next-Generation Sequencing (NGS), and the suboptimal reliability of immunohistochemistry (IHC) as a surrogate. This gap between research evidence and clinical practice represents a critical barrier to risk-adapted therapy. The broad implementation of standardized and accessible genomic techniques is essential to identify patients who deserve a personalized therapeutic approach. Several clinical trials have recently explored alternative chemo-free or targeted regimens specifically tailored to TP53-mutated patients (i.e., NCT03824483, NCT03567876), with promising results. This risk-adapted approach reflects a paradigm shift in MCL management, emphasizing the need for early molecular risk assessment to guide treatment decisions. In this scenario, TP53 mutations are no longer supporting actors, but a game-changer for the prognosis and treatment of patients with MCL.

Keywords: NGS; TP53; mantle cell lymphoma; precision medicine; prognosis; standardization

DOI: https://doi.org/10.3390/jcm14238480

NPJ Breast Cancer. 2025 Dec 12.

Stromal fibroblastic mutant Trp53 promotes mammary tumor development via enhanced secretion of paracrine factors.

Bin Liu, Shunbin Xiong, Abie Williams-Villalobo, Gilda Chau, Yuan Qi, Hehua Chen, Carenza Johnson, Dhruv Chachad, Joy McDaniel, Xiaoping Su, Adel K El-Naggar, Guillermina Lozano, Yun Zhang.

Mutations in the tumor suppressor gene TP53 have been identified in breast cancer-associated fibroblasts and are associated with poor patient prognosis. However, the functional impact of fibroblastic mutant p53 on breast cancer development remains unclear. To investigate this, we compared female mice harboring HER2-driven mammary tumors with a fibroblast-specific Trp53 mutation (NP) to those with wild-type fibroblastic Trp53 (N). NP mice exhibited significantly shorter median tumor-free survival than N mice. RNA sequencing of NP and N tumors and mammary glands revealed numerous differentially expressed genes (DEGs) between tumors and the corresponding glands in both genotypes. Notably, the NP tumors showed enrichment of several signaling pathways, including PI3K/AKT/mTOR. Additionally, fifteen DEGs encoding secreted proteins were identified between NP and N mammary glands. Among these, SAA1 and SAA2 were also upregulated in human breast tumors with mutant TP53 compared to those with wild-type TP53. Previous studies have implicated SAA1, SAA2, and THBS4 in promoting tumor progression via the PI3K/AKT pathway. Consistently, supplementing primary HER2-positive tumor cultures with recombinant SAA1, SAA2, or THBS4 peptides enhanced tumor cell proliferation and migration. Together, these findings uncover a mechanism by which fibroblastic mutant p53 promotes mammary tumorigenesis-through upregulating secretory proteins such as SAA1, SAA2, and THBS4 in the stroma, thereby enhancing PI3K/AKT signaling and tumor progression.

DOI: https://doi.org/10.1038/s41523-025-00876-y

Cell Death Dis. 2025 Dec 11.

Mice carrying nonsense mutant p53 develop frequent multicentric or metastatic tumors.

Charlotte Strandgren, Veronica Rondahl, Ann-Sophie Oppelt, Susanne Öhlin, Angelos Heldin, Klas G Wiman.

The TP53 tumor suppressor gene is mutated in a large fraction of human tumors. Close to 11% of TP53 mutations are nonsense mutations, causing premature termination of protein synthesis and expression of truncated inactive p53 protein. The most common TP53 nonsense mutation in human cancer is R213X. To study the impact of TP53 nonsense mutations in vivo, we generated mice harboring the Trp53 nonsense mutation R210X that corresponds to human TP53-R213X. Initially, Trp53R210X mice appear phenotypically normal, although the proportion of female Trp53R210X/R210X mice is dramatically reduced. Female homozygous mice are poor breeders and remain smaller and lighter than female heterozygous and wildtype littermates. Trp53R210X/R210X mice start to show tumors at 2.5 months of age, and their maximal lifespan is 8.5 months. Trp53R210X/+ mice present tumors from 9 months of age, and by 16.5 months of age 50% of all heterozygous mice have developed overt tumors. 71% of tumors from Trp53R210X/+ mice show loss of heterozygosity (LOH). Homozygous mice develop hematopoietic and mesenchymal tumors, most commonly T-cell lymphoma and leiomyosarcoma, and heterozygous mice develop hematopoietic, mesenchymal, epithelial and sex cord tumors, most commonly osteosarcoma and leiomyosarcoma. The tumor phenotype is similar to that of Trp53-null and Trp53-missense knock-in mice, although the Trp53R210X/R210X mice have a high rate of multicentric or metastatic tumors, and Trp53R210X/+ mice have a longer overall survival than Trp53R172H/+ missense mutant knock-in mice. Treatment of T-cell lymphoma cells from Trp53R210X/R210X mice with aminoglycoside G418 induces expression of full-length functional p53 and apoptotic cell death. Our new unique mouse model will allow further studies of the effects of Trp53 nonsense mutation in a multi-organ system and serve as a model for the Li-Fraumeni syndrome (LFS). It will also be valuable for preclinical evaluation of novel therapeutic strategies for targeting TP53 nonsense mutations in cancer.

DOI: https://doi.org/10.1038/s41419-025-08290-9