Point-Counterpoint
Context Matters: TP53 Alterations in Myeloid Neoplasms Free

The p53 protein plays a pivotal role in maintaining genomic integrity in hematopoietic stem and progenitor cells. TP53 mutations can be detected in association with a broad spectrum of myeloid proliferations, ranging from clonal hematopoiesis, often in the context of cytotoxic stress or aging, to high-risk myeloid neoplasms. While TP53 alterations confer adverse risk in myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML), emerging data underscore that the impact of pathogenic TP53 variants (mutations) is dependent on concurrent biologic factors and the clinicopathologic context.

TP53 mutations can be detected across a continuum from clonal hematopoiesis of indeterminate potential to high-risk MDS and AML. Although relatively infrequent in healthy aging, TP53-mutant clones can arise as part of clonal hematopoiesis and often expand under stress conditions.^1,2  Such clones can survive cytotoxic therapy and later give rise to secondary myeloid neoplasms.²  These data underscore that a TP53 mutation alone does not inevitably cause acute leukemia, and additional selective pressures and cooperating genetic alterations are often required for malignant transformation. Key contextual factors include allelic state (multi-hit vs. single-hit), variant allele frequency (VAF), coexisting mutations and cytogenetic abnormalities, disease type, and history of exposure to cytotoxic therapy. Together, these factors critically modulate the impact of mutant p53 on disease behavior and outcomes.

TP53 mutations and/or allelic copy number deletions occur in 5% to 15% of MDS and AML cases.³  Studies in MDS have shown that multi-hit TP53 inactivation, defined by multiple mutations or a mutation plus deletion/copy-neutral loss of heterozygosity involving the TP53 gene locus on chromosome 17p, can define a uniquely aggressive disease subset with dismal outcomes.⁴  In contrast, single-hit TP53 mutations — particularly with low VAF — may carry less aggressive clinical implications.^5,6  Similarly, in a large, single-institution study of AML patients with TP53 mutations, Mehrnoosh Tashakori, MD, PhD, and colleagues demonstrated that information about copy number status and p53 protein expression add important refinement across the biological spectrum of the disease.⁷ 

Considering the above background, the fifth edition of the World Health Organization classification of hematolymphoid tumors (WHO-HAEM5) adopted a nuanced approach when it comes to TP53 alterations in myeloid neoplasms. WHO-HAEM5 introduces "MDS with biallelic TP53 inactivation" as a distinct entity but does not recognize TP53 mutation as an AML-defining genetic abnormality. Most AML cases harboring TP53 mutations are classified as "AML, myelodysplasia-related" (AML-MR) under WHO-HAEM5, because the majority of such cases have a complex karyotype and/or meet other diagnostic criteria of AML-MR.⁸  This framework incorporates TP53 status as a prognostic modifier in AML, not a sole defining diagnostic criterion.⁷  Put differently, a framework that defines an AML type based solely on the presence of a TP53 mutation (VAF >10%) risks masking significant biologic heterogeneity in return for capturing an aggressive disease subset. Such an approach conflates cancer classification with risk stratification. For instance, patients with monoallelic TP53 mutations and otherwise favorable features may be inappropriately grouped with multi-hit, complex karyotype cases, despite differing prognoses and potential treatment responses. The approach would also deprecate AML types such as, for example, acute erythroid leukemia, which have biologic alterations and potential therapeutic vulnerabilities that are distinct from p53 alterations.⁹ 

Recent evidence confirms that TP53-mutated myeloid neoplasms are not biologically homogeneous. Mutation type, VAF, allelic configuration, and coexisting genomic lesions must be considered to accurately risk-stratify patients and guide therapy. Ultimately, TP53 status must be interpreted in context — as a powerful but not standalone determinant of disease biology, classification, and prognosis in MDS and AML. Put differently, when it comes to TP53 alterations in myeloid neoplasms, the devil is indeed in the details.

Dr. Khoury indicated no relevant conflicts of interest.