Biallelic TP53 inactivation as a key factor in leukemic transformation.
March 25, 2026
New Horizons in Leukemia Research: Focus on Selected Papers
Treatment-related
myeloid neoplasms (t-MN) are among the most serious complications of
chemotherapy or radiation therapy. Patients with TP53-mutant clonal
hematopoiesis (CH) are at a particularly high risk of developing
treatment-related acute myeloid leukemia (AML) or myelodysplastic neoplasm (MDS).
However, the role of TP53 allelic status—that is, whether one or both TP53
alleles are mutated in an affected individual—in the development of leukemia is
not well understood and is currently not consistently accounted for in current
classification systems, such as those of the WHO and ICC.
Researchers
at the University Hospital of Zurich developed novel murine in vitro and in
vivo models that allow precise control of the allelic status of Trp53,
the murine homolog of human TP53, in hematopoietic stem and progenitor
cells (HSPCs). These models enable the first-time investigation of how mono- or
biallelic Trp53 mutations influence clonal expansion, genomic stability,
and leukemic transformation under controlled conditions.
Study results in detail
- Clonal Fitness: Both mono- and biallelic Trp53 mutations provided an advantage to HSPCs over wild-type cells in the presence of DNA damage. Biallelic mutants exhibited the strongest clonal dominance.
- Genomic integrity: Only biallelic Trp53 mutations resulted in genomic instability and large-scale copy number changes. Genomic integrity was preserved in the case of monoallelic mutations.
- Malignant transformation: Only HSPCs with biallelic Trp53 inactivation transformed in vitro and developed aggressive acute erythroid leukemias with complex karyotypes in vivo. This finding reflects the clinical association between biallelic TP53 mutations and complex karyotypes. Mice with initial monoallelic mutations only developed AML after the spontaneous loss of the wild-type allele (LOH).
- Non-mutational p53 inactivation: Overexpression of MDM2, the primary negative regulator of p53, replicated the effects of the biallelic state in cells with a monoallelic Trp53 mutation, including genomic instability and transformational potential. This provides a possible explanation for clinical cases with an apparent monoallelic TP53 mutation but a typical biallelic phenotype.
Conclusion
This study
used a mouse model to provide evidence that biallelic TP53 mutations are
a critical step in the progression from premalignant clonal hematopoiesis to
treatment-induced AML or MDS. The data support classifying biallelic TP53-mutated
AML/MDS as a distinct clinical entity, and they highlight the importance of
accurately determining TP53 allelic status for risk stratification.
Reference
Fullin J et al. The pathogenesis of therapy-related myeloid
neoplasms from TP53-mutant clonal hematopoiesis. Leukemia 2026;40:279–292. https://doi.org/10.1038/s41375-025-02839-5.
The author
"Do you have any questions regarding this study? Do not hesitate to contact me!"
Dr. rer. nat. Constanze Kühn