Study Links p53 Dysfunction to MDS Risk and Response

Nonmutational dysfunction of the p53 protein in patients with myelodysplastic syndromes (MDS) may play a critical role in disease progression, opening the door to a more nuanced, mechanistic classification of myeloid neoplasms. This is according to findings from a retrospective study published in Journal of Clinical Oncology.

“There is no question that MDS patients with TP53 mutation represented the molecular cohort with the most negative outcomes and urgent need for novel therapy. This study highlights another rare group of patients that although negative for TP53 mutation have the same p53 dysfunction and poor outcomes supporting potential inclusion of this group in novel clinical trials,” commented study coauthor David Sallman, MD, of H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, in remarks forwarded to Heme Today.

The study assessed a cohort of 6,204 patients with MDS. For 109 patients, tumor cell RNA sequencing information was available, and 77 patients had high-dimensional phenotyping of immune cells. The study included 914 patients with MDS and acute myeloid leukemia (AML) who had undergone clinical, genomic, and transcriptomic annotation at diagnosis and 15 patients with MDS from whom bone marrow samples for single-cell analysis were collected at diagnosis and on progression to AML. The prevalence of TP53 mutation in the total cohort was 10.1%.

Regarding MDS and p53 dysfunction based in TP53 mutations, the researchers found that monoallelic and biallelic TP53 inactivation was linked to disease stages in a multihit process through MDS disease progression. Moreover, biallelic TP53 inactivation was a strong driver of this progression and identified very-high-risk disease in patients irrespective of variant allele frequency.

In the cohort, 5% of patients had MDS with p53 dysfunction that was not mutation based. The researchers found, on histochemistry, that these patients had hyperexpression of abnormal p53 protein in bone marrow progenitor cells and poor outcomes and that conventional prognostic scoring does not effectively reveal the high risk of this disease type.

In these patients with nonmutational p53 dysfunction, the researchers observed several upstream p53 signaling aberrations and downstream dysregulation of p53 target genes. They also discovered that a small group of patients had significantly increased expression of the negative p53 regulator MDM2 gene.

Overall, the data point to a potential link between p53-related pathways, chronic inflammation, and immune escape, raising novel questions about how these processes drive the tumor microenvironment. Researchers recommend that future studies explore therapeutic solutions for p53 dysfunction in MDS.

“Additionally, this study highlights the profound adverse immune microenvironment for these patients that likely is a major driver of the negative outcomes and ideally will be therapeutically targeted in the near future,” Dr. Sallman wrote.

Reference

Zampini M, et al. J Clin Oncol. Published online May 2, 2025. doi:10.1200/JCO-24-02394. https://ascopubs.org/doi/10.1200/JCO-24-02394