Acute Myeloid Leukemia (AML) is a cancer of the blood and bone marrow characterized by the rapid, uncontrolled proliferation of immature white blood cells. This aggressive disease arises from the accumulation of genetic changes within hematopoietic stem or progenitor cells. These changes are typically acquired during a person’s lifetime, meaning they are somatic and not inherited. AML is highly heterogeneous, presenting a wide spectrum of clinical outcomes and responses to therapy. Understanding specific genetic mutations is fundamental, as molecular findings guide diagnosis, prognosis, and treatment selection.
The Genetic Basis of Acute Myeloid Leukemia
The development of AML is a step-wise process driven by somatic mutations affecting two major classes of genes. The first class involves oncogenes, which are functionally altered to gain an abnormal, overactive function. Mutations in oncogenes promote cell proliferation and enhance survival by constitutively activating growth signaling pathways. These gain-of-function changes provide an advantage to the leukemic cell clone, causing excessive multiplication.
The second class consists of tumor suppressor genes, whose normal function is to regulate cell division and induce cell death. Mutations in these genes lead to a loss of function, removing the cell’s internal brakes on growth and maturation. The combination of these two classes of mutations disrupts normal blood cell production (hematopoiesis). This disruption blocks the differentiation of myeloid precursor cells, causing an accumulation of non-functional, immature blast cells in the bone marrow and peripheral blood.
Identifying Critical AML Mutation Categories
AML mutations are grouped by their primary biological impact, reflecting the dual-hit hypothesis of leukemogenesis. Class I mutations primarily confer a proliferative advantage, driving cell growth and survival signaling. The most common example is the FLT3 gene, a receptor tyrosine kinase mutated in nearly one-third of AML cases. Two main types exist: the FLT3 Internal Tandem Duplication (ITD) and the Tyrosine Kinase Domain (TKD) point mutation. The ITD mutation leads to constitutive activation of the receptor, resulting in aggressive cell proliferation. Another Class I mutation is in the KIT gene, where mutations in the Exon 17 region cause aberrant phosphorylation and growth signaling.
Class II mutations primarily impair the normal differentiation process of blood cells. A prime example is the NPM1 gene mutation, found in about one-third of adult AML cases. This mutation causes the nucleophosmin protein to be aberrantly localized in the cytoplasm instead of shuttling between the nucleus and cytoplasm. This mislocalization disrupts the protein’s tumor suppressor ability, hindering the maturation of the myeloid lineage. The CEBPA gene, a transcription factor directing granulocyte differentiation, is also a Class II target. The prognostically relevant biallelic mutation involves two separate mutations that block the cell’s ability to mature, often by producing a truncated, dominant-negative protein.
A third category involves mutations that alter cellular metabolism and epigenetic regulation, such as those in the IDH1 and IDH2 genes. These mutations cause the enzyme to gain a new function, converting the normal metabolic molecule alpha-ketoglutarate into the abnormal substance 2-hydroxyglutarate (2-HG). This oncometabolite interferes with numerous enzymes that regulate gene expression, leading to widespread epigenetic changes and contributing to the block in cell differentiation.
Using Mutations for Prognosis and Risk Stratification
Genetic findings are translated into a clinical prognosis using standardized criteria established by the European LeukemiaNet (ELN). This system stratifies patients into three groups—Favorable, Intermediate, and Adverse—which directly influences treatment intensity and long-term outlook. The Favorable risk category includes cases with an NPM1 mutation but without an accompanying FLT3-ITD mutation, and those with in-frame mutations affecting the basic leucine zipper (bZIP) domain of CEBPA. These patients tend to have higher rates of complete remission and lower rates of relapse with standard chemotherapy.
The Intermediate risk category includes AML with a FLT3-ITD mutation, regardless of the mutant to wild-type allele ratio or the presence of a co-occurring NPM1 mutation. While FLT3-ITD is associated with a higher relapse risk, modern targeted therapy has tempered its negative impact. The Adverse risk category is reserved for patients whose leukemia is driven by aggressive genetic changes. This group includes AML with a TP53 mutation, which is often linked to a complex karyotype and a poor response to conventional therapy. Mutations in myelodysplasia-related genes, such as ASXL1, RUNX1, and EZH2, also classify patients into the Adverse risk group due to their association with resistance and poor survival.
Mutation-Driven Targeted Treatment Approaches
The identification of specific mutations has ushered in the era of targeted therapy in AML, where drugs counteract the molecular change caused by the mutation. For patients with FLT3 mutations, tyrosine kinase inhibitors (TKIs) block the hyperactive signaling of the mutated receptor. Midostaurin, a first-generation TKI, is approved alongside standard intensive chemotherapy in newly diagnosed patients. Gilteritinib, a potent second-generation inhibitor, is used for patients with relapsed or refractory FLT3-mutated disease, demonstrating superior efficacy by targeting both the ITD and TKD mutations.
The metabolic mutations in IDH1 and IDH2 are also targeted by specific inhibitors. Ivosidenib targets the mutant IDH1 enzyme, while Enasidenib targets the mutant IDH2 enzyme. These drugs function by binding to the mutant protein and preventing the production of the aberrant oncometabolite 2-HG. Reducing the level of 2-HG allows the normal differentiation pathway to resume, reversing the differentiation block. The presence of a targetable mutation also guides the initial choice between intensive chemotherapy and lower-intensity regimens, particularly for older or less fit patients.
Methods for Detecting AML Mutations
Accurate genetic testing is fundamental to modern AML management, relying on a combination of laboratory techniques. Conventional karyotyping is the oldest method, used to analyze the entire set of chromosomes to detect large-scale structural changes, such as translocations and inversions. These changes, like the fusion gene created by t(8;21), are associated with specific disease subtypes and risk groups.
Polymerase Chain Reaction (PCR) is utilized to quickly detect specific, known “hot spot” mutations, such as the FLT3-ITD and NPM1 insertions. Its high sensitivity makes PCR an important tool for monitoring measurable residual disease (MRD), detecting small numbers of remaining leukemic cells after treatment. Next-Generation Sequencing (NGS) allows for the simultaneous analysis of multiple genes relevant to AML. NGS detects single nucleotide variants, small insertions, and deletions across a broad panel of genes, providing the detailed mutational profile necessary to apply the current ELN risk stratification guidelines.