TP53-Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Biology, Current Therapy, and Future Directions

Abstract

TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) form a distinct group of myeloid disorders with dismal outcomes. TP53-mutated MDS and AML have lower response rates to either induction chemotherapy, hypomethylating agent-based regimens, or venetoclax-based therapies compared with non-TP53-mutated counterparts and a poor median overall survival of 5 to 10 months. Recent advances have identified novel pathogenic mechanisms in TP53-mutated myeloid malignancies, which have the potential to improve treatment strategies in this distinct clinical subgroup. In this review, we discuss recent insights into the biology of TP53-mutated MDS/AML, current treatments, and emerging therapies, including immunotherapeutic and nonimmune-based approaches for this entity.

Significance: Emerging data on the impact of cytogenetic aberrations, TP53 allelic burden, immunobiology, and tumor microenvironment of TP53-mutated MDS and AML are further unraveling the complexity of this disease. An improved understanding of the functional consequences of TP53 mutations and immune dysregulation in TP53-mutated AML/MDS coupled with dismal outcomes has resulted in a shift from the use of cytotoxic and hypomethylating agent-based therapies to novel immune and nonimmune strategies for the treatment of this entity. It is hoped that these novel, rationally designed combinations will improve outcomes in this area of significant unmet need.

Figure 1.

Different subunits of the p53 are coded by a gene located on chromosome 17p13.1. p53 resides over a highly connected hub involving multiple signal transduction pathways, including DNA damage response, oncogene activation, cellular stress, and its positive and negative regulators. In turn, p53 regulates numerous key cellular processes including cell cycling, genomic stability, cell metabolism, differentiation, proliferation, apoptosis, senescence, and others. In addition, downstream signaling through p53 influences the tumor microenvironment through a direct effect on several immunologic targets. APC, antigen-presenting cell; NK, natural killer; Treg, regulatory T cell.

Figure 2.

Novel therapies for TP53-mutated MDS and AML. Cell-extrinsic immunotherapeutic approaches include targeting cell-surface markers including LSC markers, macrophage and T-cell checkpoints, bispecific engagers, and adoptive cellular therapies including unmodified and chimeric antigen receptor–modified cells. Cell-intrinsic approaches include mutant p53 reactivators, mutant p53 degraders, metabolism-targeting agents, GSPT1 degraders, and others. Ab, antibody; ADCC, antibody-dependent cell-mediated cytotoxicity; BiTE, bispecific T-cell engager; NK, natural killer; TCR, T-cell receptor; Treg, regulatory T cell; TriKE, trispecific killer cell engager.