Acute promyelocytic leukemia (APL) is an aggressive subtype of acute myeloid leukemia (AML), a cancer affecting the blood and bone marrow. This condition prevents immature white blood cells, specifically promyelocytes, from maturing into functional infection-fighting cells, leading to their uncontrolled accumulation. APL is overwhelmingly driven by one definable genetic event that dictates the disease’s biology and responsiveness to targeted treatment.
The Defining Genetic Translocation
The cause of APL is traced to a specific rearrangement within the cell’s genetic material, known as a chromosomal translocation. A translocation occurs when two different chromosomes break and swap segments with each other. In over 95% of APL cases, this involves a swap between chromosome 15 and chromosome 17, designated as t(15;17).
This exchange joins the PML gene (Promyelocytic Leukemia) on chromosome 15 with the RARA gene (Retinoic Acid Receptor Alpha) on chromosome 17. This fusion creates a single, abnormal oncogene called PML-RARA, which produces a novel protein that acts as the primary driver of the leukemia. The PML-RARA fusion gene is the hallmark of APL. This genetic signature is typically acquired during a person’s lifetime, meaning it is a somatic mutation that is not inherited from parents.
How the Fusion Protein Blocks Cell Maturation
The normal Retinoic Acid Receptor Alpha (RARA) protein plays a fundamental role in regulating gene expression necessary for the maturation of myeloid blood cells. When the body needs mature white blood cells, retinoic acid binds to the RARA receptor, signaling the cell to complete its differentiation. The abnormal PML-RARA fusion protein retains the binding site for retinoic acid but functions as a potent transcriptional repressor that blocks this differentiation signal.
The fusion protein forms complexes with other proteins, recruiting co-repressors that silence the genes required for the promyelocyte to mature. It acts like a powerful, stuck brake on the process of cell development. The PML-RARA protein is also much more resistant to activation by natural levels of retinoic acid compared to the normal RARA receptor.
The presence of the PML-RARA protein also disrupts the function of the normal PML protein, which acts as a tumor suppressor involved in programmed cell death and regulating cell growth. By interfering with both the differentiation pathway of RARA and the tumor-suppressing function of PML, the fusion protein drives the proliferation of immature leukemia cells.
External Factors and Predisposition
The event that creates the t(15;17) translocation is most often spontaneous, meaning it arises de novo without an identifiable external cause. APL is generally not considered an inherited condition. Factors that increase the general risk of developing leukemia may contribute to the rare occurrence of this genetic event. Exposure to certain environmental toxins, such as the organic solvent benzene, has been linked to an increased risk of acute myeloid leukemia overall. Occupational exposure and cigarette smoking are also recognized as potential risk factors for APL.
Therapy-Related APL
A small fraction of APL cases are classified as therapy-related APL, which develops following previous treatment for a different cancer. Exposure to specific types of chemotherapy, particularly topoisomerase II inhibitors and alkylating agents, or prior radiation therapy, can damage DNA and increase the likelihood of chromosomal rearrangements. These antecedent exposures represent a known predisposition for the disease, although a direct cause-and-effect for the t(15;17) translocation is less common in therapy-related cases than in other AML subtypes.