Common Driver Mutations in AML: Biological Impact, Clinical Considerations, and Treatment Strategies

Abstract

Next-generation sequencing of samples from patients with acute myeloid leukemia (AML) has revealed several driver gene mutations in adult AML. However, unlike other cancers, AML is defined by relatively few mutations per patient, with a median of 4-5 depending on subtype. In this review, we will discuss the most common driver genes found in patients with AML and focus on the most clinically relevant ones that impact treatment strategies. The most common driver gene mutations in AML occur in NPM1 and FLT3, accounting for ~30% each. There are now targeted therapies being tested or already approved for these driver genes. Menin inhibitors, a novel targeted therapy that blocks the function of the menin protein, are in clinical trials for NPM1 driver gene mutant AML after relapse. A number of FLT3 inhibitors are now approved for FLT3 driver gene mutant AML in combination with chemotherapy in the frontline and also as single agent in relapse. Although mutations in IDH1/2 and TP53 only occur in around 10-20% of patients with AML each, they can affect the treatment strategy due to their association with prognosis and availability of targeted agents. While the impact of other driver gene mutations in AML is recognized, there is a lack of data on the actionable impact of those mutations.

Keywords: AML; FLT3; IDH; NPM1; TP53; driver mutations.

Figure 1

Key Driver Mutations and Cellular Pathways in AML Pathogenesis. (a) Mutant IDH1 (cytoplasm) and IDH2 (mitochondria) enzymes produce elevated levels of the oncometabolite 2-hydroxyglutarate (2-HG), which inhibits chromatin-modifying enzymes such as histone and DNA demethylases, leading to a block in cellular differentiation, contributing to oncogenesis. (b) FLT3-ITD mutations lead to constitutive activation of the FLT3 receptor, triggering downstream signaling pathways including RAF/MEK/ERK, PI3K/AKT, and STAT pathways. This continuous signaling promotes cell proliferation, survival, and differentiation blockade, contributing to leukemogenesis. (c) TP53 mutations in AML impair the tumor suppressor functions of p53, which is activated in response to DNA damage stimuli, leading to disrupted apoptosis, senescence, DNA repair, and cell cycle arrest. This results in unchecked cell proliferation, genomic instability, and enhanced leukemogenesis. (d) In AML with a mutated NPM1 gene, NPM1 is aberrantly expressed in the cytoplasm due to increased nuclear export (solid arrows) surpassing nuclear import (dotted arrow). Mutant NPM1 fails to stabilize TP53 in the nucleoplasm, which normally modulates stress response and growth suppression.