Mutation in Acute Myeloid Leukemia: An Old Foe Revisited.

INTRODUCTION

is the most commonly mutated gene in human cancers and was the first tumor suppressor gene to be discovered in the history of medical science. Mutations in the gene occur at various genetic locations and exhibit significant heterogeneity among patients. Mutations occurring primarily within the DNA-binding domain of result in the loss of the p53 protein's DNA-binding capability. However, a complex phenotypic landscape often combines gain-of-function, dominant negative, or altered specificity features. This complexity poses a significant challenge in developing an effective treatment strategy, which eradicates -mutated cancer clones. This review summarizes the current understanding of mutations in AML and their implications. mutation in AML: In patients with acute myeloid leukemia (AML), six hotspot mutations (R175H, G245S, R248Q/W, R249S, R273H/S, and R282W) within the DNA-binding domain are common. mutations are frequently associated with a complex karyotype and subgroups of therapy-related or secondary AML. The presence of mutation is considered as a poor prognostic factor. -mutated AML is even classified as a distinct subgroup of AML by itself, as -mutated AML exhibits a significantly distinct landscape in terms of co-mutation and gene expression profiles compared with wildtype (WT)- AML.

CLINICAL IMPLICATIONS

To better predict the prognosis in cancer patients with different mutations, several predictive scoring systems have been proposed based on screening experiments, to assess the aggressiveness of -mutated cancer cells. Among those scoring systems, a relative fitness score (RFS) could be applied to AML patients with mutations in terms of overall survival (OS) and event-free survival (EFS). The current standard treatment, which includes cytotoxic chemotherapy and allogeneic hematopoietic stem cell transplantation, is largely ineffective for patients with -mutated AML. Consequently, most patients with -mutated AML succumb to leukemia within several months, despite active anticancer treatment. Decitabine, a hypomethylating agent, is known to be relatively effective in patients with AML. Numerous trials are ongoing to investigate the effects of novel drugs combined with hypomethylating agents, -targeting agents or immunologic agents.

CONCLUSIONS

Developing an effective treatment strategy for -mutated AML through innovative and multidisciplinary research is an urgent task. Directly targeting mutated holds promise as an approach to combating -mutated AML, and recent developments in immunologic agents for AML offer hope in this field.