Are TP53 mutations all alike?

TP53 is mutated in 10 to 15% of cases of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and is associated with a previous exposure to cytotoxic therapy, complex cytogenetic abnormalities, and a poor prognosis. Recent data have established the importance of TP53mutant allele status, the determination of which requires specific genetic testing. Compared with monoallelic disease, multihit TP53mutant AML/MDS is associated with chromosomal abnormalities and decreased overall survival. Most TP53 mutations are missense mutations that localize to the DNA binding domain. Hotspot mutations involving residues R175, Y220, G245, R248, R273, or R282 represent approximately 35% of all TP53 missense mutations in AML/MDS. There is evidence that these hotspot mutations may have dominant negative or gainoffunction properties. Here we review this evidence and discuss its potential impact on patient outcomes and clinical management.