Introduction:

Acute Myeloid Leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of immature myeloid cells in the bone marrow. While the precise etiology of AML remains incompletely understood, it is believed to arise from the interplay of genetic predisposition and environmental exposures. This article delves into the multifactorial etiology of AML, exploring genetic mutations, environmental carcinogens, and other risk factors implicated in disease pathogenesis.

Genetic Mutations:

• Somatic Mutations: AML is characterized by the accumulation of somatic mutations in hematopoietic stem or progenitor cells, leading to uncontrolled proliferation and impaired differentiation. Common mutations include alterations in genes encoding transcription factors (e.g., RUNX1, CEBPA), signaling proteins (e.g., FLT3, KIT), epigenetic regulators (e.g., DNMT3A, IDH1/2), and tumor suppressors (e.g., TP53).
• Germline Predisposition: In some cases, AML may be associated with inherited genetic syndromes, such as familial platelet disorder with predisposition to AML (FPD/AML), Down syndrome, Li-Fraumeni syndrome, and Fanconi anemia, among others. These syndromes confer an increased risk of developing AML due to germline mutations in specific genes involved in hematopoiesis and DNA repair pathways.

Environmental Carcinogens:

• Chemical Exposures: Exposure to environmental carcinogens, such as benzene, ionizing radiation, chemotherapy agents, and certain industrial chemicals, has been implicated in the pathogenesis of AML. Benzene, in particular, is a well-established leukemogen associated with occupational and environmental exposures.
• Cigarette Smoking: Cigarette smoking is a recognized risk factor for AML, with smokers having a higher incidence of AML compared to non-smokers. The carcinogens present in tobacco smoke, including benzene and polycyclic aromatic hydrocarbons, contribute to leukemogenesis.

Other Risk Factors:

• Age: AML incidence increases with age, with the majority of cases diagnosed in older adults. Aging is associated with the accumulation of somatic mutations and clonal hematopoiesis, predisposing individuals to the development of AML.
• Prior Chemotherapy or Radiation Therapy: Previous exposure to cytotoxic chemotherapy or radiation therapy for other malignancies increases the risk of secondary AML (sAML), also known as therapy-related AML (tAML). These treatments damage hematopoietic stem cells and disrupt normal hematopoiesis, predisposing to leukemic transformation.

Conclusion:

The etiology of Acute Myeloid Leukemia (AML) is multifactorial, involving a complex interplay of genetic mutations, environmental carcinogens, and other risk factors. Understanding the etiological factors underlying AML pathogenesis is essential for elucidating disease mechanisms, identifying high-risk populations, and developing targeted prevention and intervention strategies.

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