A06 | TP53 in myeloid neoplasms

Abstract

The TP53 gene encodes the transcription factor p53, a central regulator of genomic integrity and stem-cell fitness. Loss of TP53 function, through genetic mutations and/or deletion of chromosome 17, disrupts DNA damage checkpoints, promotes tolerance to genotoxic stress, and represents a key prognostic factor in myeloid neoplasms (MN). Across MN phenotypes, TP53-driven diseases (most commonly therapy-related neoplasms and myelodysplastic syndromes (MDS)) are characterized by an aggressive clinical course and high-risk chromosomal aberrations ¹.

In acute myeloid leukemia (AML) and MDS, TP53 mutations define one of the most adverse-risk biological subsets, associated with primary chemoresistance or only transient responses to hypomethylating agents and very poor overall survival ^1-3. Accordingly, contemporary classification systems recognize TP53 alterations as a distinct disease entity or molecular category ^4-5. Despite these biological underpinnings, from a clinical perspective, TP53-mutated AML/MDS remain an urgent unmet medical need, as no current or investigational therapy consistently achieves durable disease control or long-term survival ¹(Table 1).

Mechanistic dissection of TP53-driven leukemogenesis has recently highlighted the critical role of allelic state. Experimental in vitro and in vivo models show that monoallelic TP53 alterations confer selective clonal fitness under cytotoxic or radiation-induced stress with relatively limited genomic instability, whereas biallelic inactivation leads to defective p53 signaling, large-scale copy-number alterations, and acquisition of autonomous self-renewal culminating in leukemic transformation ⁶. Despite these biological insights, the clinical implications of TP53 biallelic status remain a matter of debate ^7-9.

Consistent with these mechanisms, TP53 mutations also confer adverse prognosis in myelodysplastic/myeloproliferative neoplasm (MDS/MPN) overlap syndromes. In chronic myelomonocytic leukemia (CMML), TP53 alterations are among the strongest predictors of inferior survival and leukemic transformation ¹⁰, while in MDS/MPN not otherwise specified (NOS) they define a biologically distinct high-risk molecular subtype ¹¹.

Beyond acute phenotypes, TP53 mutations adversely affect outcomes in (MPN), including essential thrombocythemia and myelofibrosis ^12-13. Recent data suggest a context-dependent effect in MPN, where male sex, multi-hit status, absence of transplantation, and advanced versus chronic disease phase predict worse outcomes, findings further confirmed in the transplantation setting.

Collectively, TP53 alterations represent a high-risk biological feature across myeloid neoplasm phenotypes. Further studies are required to clarify the leukemogenic processes driven by TP53 dysfunction and to develop effective disease-modifying therapeutic strategies for this critical unmet clinical need.

References

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