Point-Counterpoint
The Great Equalizer: TP53 Alterations in Myeloid Neoplasms Free

The tumor suppressor TP53 gene located at chromosome 17p13 encodes the p53 protein, which is critical in regulating hematopoietic cell proliferation and differentiation. Somatic mutations in TP53 inactivate its tumor suppressor activity and underlie approximately 10% of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) cases. The majority of TP53-mutated MDS and AML cases exhibit resistance to currently available therapies and a markedly poor prognosis compared to their TP53 wild-type counterparts.

Population-based studies have shown that TP53 mutations are among the more common in clonal hematopoiesis of indeterminate potential (CHIP) and are often stable at a low level for many years without sequelae.^1,2  The allelic state of TP53 mutations underlies its pathogenesis in myeloid neoplasia: while single (monoallelic) mutations occur in lower-risk MDS and do not confer adverse risk, multi-hit TP53 mutations (in which both copies of the gene are inactivated by mutation and/or loss) are associated with genetic instability and highly aggressive disease.³  Expansion of TP53 clones appears to be driven by cytotoxic therapies that select for TP53-mutated hematopoietic clones;⁴  however, approximately half of TP53-mutated myeloid neoplasms occur in patients without such history.⁵  The association of TP53 mutations with complex karyotypes and dismal prognosis is seen in both MDS and AML and in both de novo and therapy-related disease. In patients with MDS undergoing stem cell transplant, TP53 is the single most important adverse genetic prognostic factor.⁶ 

The International Consensus Classification (ICC) introduced new entities defined by TP53 mutation in both MDS and AML, which supersede all other disease subtypes.⁷  These are considered together as a group of “ TP53-mutated myeloid neoplasms” and are subdivided based on blast counts as MDS, MDS/AML, and AML. This approach is supported by recent unsupervised molecular classification studies in which TP53 mutation (and/or complex karyotype) emerges as a major genetic classifier in AML^8,9  and also as a single genomically-defined group among all myeloid neoplasms.¹⁰  Therapy-relatedness is no longer used as a major classifier in the ICC, as the historically poor prognosis of therapy-related MDS and AML appear to largely reflect their common association with TP53 mutations.¹¹ 

The rationale for unifying TP53-mutated myeloid neoplasms under one umbrella is to facilitate clinical trials and treatment strategies to target this uniformly aggressive group of diseases. To date, numerous therapeutic approaches have proved futile in improving their dismal outcome, including therapies that target the p53 mutant protein itself.¹²  A multi-hit configuration is more common in cases with increased blast counts, and some evidence suggests that monoallelic TP53 mutations may have a similar prognosis to multi-hit mutations in AML and MDS with at least 10% blasts.¹³  For this reason, the ICC includes both monoallelic and multi-hit TP53 mutations in the definitions of TP53-mutated MDS/AML and AML. However, to avoid overdiagnosis in cases with multiple small TP53 CHIP clones, the ICC requires a minimum variant-allele fraction (VAF) of 10% for all TP53-mutated myeloid neoplasms.⁷ 

The ICC introduced a broad category of TP53-mutated myeloid neoplasms that includes both MDS and AML to delineate a group of patients with dismal prognosis. Undoubtedly, this area warrants further refinement. The minimal VAF threshold of 10% is arbitrary and may not be optimal. Assessment of monoallelic versus multi-hit TP53 status is not available in all practice settings. Additionally, some TP53 mutations may have more or less deleterious effects, warranting further study. It is hoped that unifying TP53-mutated myeloid neoplasms into an overarching disease category may help foster the discovery of desperately needed novel treatment approaches.

Dr. Hasserjian indicated no relevant conflicts of interest.