Acute Myeloid Leukemia (AML) is a cancer of the blood and bone marrow characterized by the rapid production of abnormal white blood cells. This condition arises from acquired genetic changes, or mutations, within the hematopoietic stem cells that form blood. These mutations are not inherited but develop over time, disrupting the normal development of blood cells and leading to the features of AML.
How Gene Mutations Cause AML
In healthy bone marrow, stem cells mature into functional blood cells like red blood cells, platelets, and white blood cells. This process is regulated by genes that control cell growth, division, and death. Gene mutations can interfere with this system, causing the development of AML.
Oncogenes can be compared to a “stuck gas pedal” in a car. In their normal state, these genes help regulate cell growth, but when mutated, they can become overly active, sending constant signals for cells to multiply. An example of this is the FLT3 gene, which, when mutated, promotes the rapid proliferation of leukemia cells.
Tumor suppressor genes act like the “brakes” of a cell, slowing down division or initiating cell death when necessary. Mutations that “turn off” these genes remove these controls, allowing cells to grow without restraint. This leads to the overproduction of immature white blood cells called “blasts,” which build up in the bone marrow and crowd out healthy cells.
Key Mutations and Prognostic Groups
The specific combination of gene mutations in AML cells helps determine a patient’s prognosis and guide treatment. Based on these molecular markers, hematologists classify patients into favorable, intermediate, and adverse risk groups. This classification helps predict how the disease will behave and respond to therapy.
The favorable-risk group has a better outlook and a higher likelihood of responding to standard chemotherapy. Mutations in this category include NPM1, which is found in about one-third of cases, particularly without a concurrent FLT3-ITD mutation. Another favorable marker is the presence of mutations in both copies of the CEBPA gene, referred to as biallelic CEBPA mutations.
The intermediate-risk group includes mutations not categorized as favorable or adverse. This can include mutations in the KIT gene, often found with other chromosomal changes called core-binding factor translocations. Patients with a normal cytogenetic profile who lack favorable or adverse mutations also fall into this group.
The adverse-risk group is linked to a higher chance of the leukemia resisting treatment or returning after remission. Mutations in this group include TP53, a well-known tumor suppressor found in about 10% of AML patients. Other adverse mutations include RUNX1, ASXL1, and FLT3-ITD, a specific change in the FLT3 gene.
Identifying Specific AML Mutations
To determine the AML subtype and its genetic profile, a bone marrow biopsy is performed. A small sample of bone marrow tissue and liquid is removed, usually from the hip bone. This sample is then used for specialized laboratory tests to identify the specific mutations driving the leukemia.
One test is cytogenetics, which involves examining the chromosomes within leukemia cells under a microscope. This technique allows pathologists to spot large-scale genetic changes like translocations or deletions. Certain translocations, such as the one between chromosomes 8 and 21, are associated with a more favorable prognosis.
For a more detailed analysis, molecular testing examines the DNA sequence of specific genes. Techniques like Polymerase Chain Reaction (PCR) look for known “hotspot” mutations common in AML. A more comprehensive method is Next-Generation Sequencing (NGS), which screens a large panel of genes simultaneously to identify a wide array of mutations, enabling a more precise risk classification.
Targeted Therapies Based on Mutations
The identification of specific gene mutations in AML has led to targeted therapies. This “personalized medicine” approach uses drugs designed to attack cancer cells by exploiting their genetic vulnerabilities while minimizing damage to healthy cells. These treatments offer new options and can improve outcomes for patients with particular mutations.
For AML with FLT3 mutations, which are common and associated with aggressive disease, scientists developed FLT3 inhibitors. These drugs, such as midostaurin and gilteritinib, block the activity of the mutated FLT3 protein to treat patients with this genetic marker.
Targeted therapies also exist for mutations in the IDH1 and IDH2 genes, which are involved in cellular metabolism. When mutated, these genes produce a molecule that interferes with normal cell maturation. IDH inhibitors like ivosidenib (IDH1) and enasidenib (IDH2) block these altered enzymes, allowing leukemia cells to mature more normally. These drugs are an important option for patients with these mutations, especially those who are not candidates for intensive chemotherapy.