A line in shifting sand: Can we define and target TP53 mutated MDS?

Abstract

Mutations in the tumor suppressor protein, TP53, lead to dismal outcomes in myeloid malignancies, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Recent pathological reclassifications have integrated TP53 mutated MDS and AML under a unified category of TP53 mutated myeloid neoplasms, which allows for more flexibility in treatment approaches. Therapeutic strategies have predominantly mirrored those for AML, with allogeneic stem cell transplantation emerging as critical for long-term disease control. The question remains whether there are physiological distinctions within TP53 mutated myeloid neoplasms that will significantly impact prognosis and therapeutic considerations. This review explores the unique aspects of classically defined "TP53 mutated MDS", focusing on its distinct biological characteristics and outcomes. Our current understanding is that TP53 mutated MDS and AML are globally quite similar, but as a group have unique features compared to TP53 wildtype (WT) disease. Optimizing immunotherapy and targeting vulnerabilities due to co-mutations and/or chromosome abnormalities should be the focus of future research.

Keywords: AML; Biology; MDS; TP53; Treatment.

Fig. 1. Ongoing drug development targets in high risk MDS.

Schema of active targets for drug development in high risk MDS, including TP53 mutated myeloid neoplasms with a focus on cellular immunotherapy and drugs targeting cell signaling, epigenetics, gene expression, cell cycle, apoptosis, p53 activity, proteosome activity and metabolic pathways, including mitochondria, cholesterol and NAD synthesis. Abbreviations: TGF = transforming growth factor; FLT3 = fms-like tyrosine kinase 3; ATR = ataxia telangiectasia and Rad3-related protein; PRTM5 = protein arginine methyltransferase 5; DNA = deoxyribonucleic acid; WNT = wingless/integrated; HMG-CoA = hydroxymethylglutarylcoenzyme A; NF-kB = nuclear factor kappa B; IKK = inhibitor of nuclear factor kappa B; DMAPT = dimethylamino parthenolide; NEDD8 = neural precusor cell expressed developmentally down-regulated 8; BiTE = bispecific T-cell engager; ADC = antibody drug-conjugate; SIRPa = signal regulatory protein alpha; TIM3 = T-cell immunoglobulin and mucin domain 3; IDH = isocitrate dehydrogenase; TP53 = tumor protein 53; MDM2 = murine double minute 2; NAMPT = nicotinamide phosphoribosyltransferase; BCL = B-cell leukemia/lymphoma.