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Acute myeloid leukemia (AML) is a neoplasm characterized by infiltration of the blood, bone marrow, and other tissues by proliferative, clonal, poorly differentiated cells of the hematopoietic system. These leukemias comprise a spectrum of malignancies that, untreated, are uniformly fatal. In 2016, the estimated number of new AML cases in the United States was 19,950, comprising ~1.2% of all cancer cases. AML is the most common acute leukemia in older patients, with a median age at diagnosis of 67 years. Long-term survival is infrequent; U.S. registry data report that only 27% of patients survive 5 years.
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Most cases of AML are idiopathic. Genetic predisposition, radiation, chemical/other occupational exposures, and drugs have been implicated in the development of AML, but AML cases with established etiology are relatively rare. No direct evidence suggests a viral etiology. Genome sequencing studies suggest that most cases of AML arise from a limited number of mutations that accumulate with advancing age. Indeed, genome sequencing is providing paradigm-shifting advances in our understanding of leukemogenesis. The Cancer Genome Atlas (TCGA) and other databases demonstrate that blood cells from up to 5–6% of normal individuals aged >70 years contain potentially “premalignant” mutations that are associated with clonal expansion. The additional insults that subsequently direct “premalignant” blood cells to leukemia are quite heterogeneous and still poorly understood.
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Genetic Predisposition
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Myeloid neoplasms typically occur sporadically in adults; inherited predisposition is rare. Yet, it is clear that myeloid neoplasms with germline predisposition represent an important and growing subset of disease. Germline mutations associated with increased risk of developing a myeloid neoplasm include CEBPA, DDX41, RUNX1, ANKRD26, ETV6, and GATA2 (Table 100-1). Likewise, myeloid neoplasms with germline predisposition are a feature of several well-described clinical syndromes, including bone marrow failure disorders (e.g., Fanconi anemia, Shwachman-Diamond syndrome, Diamond-Blackfan anemia), and telomere biology disorders (e.g., dyskeratosis congenita). As new mutations and associations are added to a rapidly growing list, it is increasingly clear that genetic predisposition plays a larger role than has been previously understood.
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