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.
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.
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.
TABLE 100-1WHO 2016 Classification of Myeloid Neoplasms with Germline Predisposition ||Download (.pdf) TABLE 100-1 WHO 2016 Classification of Myeloid Neoplasms with Germline Predisposition
Myeloid neoplasms with germline predisposition without a preexisting disorder or organ dysfunction
Acute myeloid leukemia with germline CEBPA mutation
Myeloid neoplasms with germline DDX41 mutationb
Myeloid neoplasms with germline predisposition and preexisting platelet disorders
Myeloid neoplasms with germline RUNX1 mutationb
Myeloid neoplasms with germline ANKRD26 mutationb
Myeloid neoplasms with germline ETV6 mutationb
Myeloid neoplasms with germline predisposition and other organ dysfunction
Myeloid neoplasms with germline GATA2 mutation
Myeloid neoplasms associated with bone marrow failure syndromes
Myeloid neoplasms associated with telomere biology disorders
Myeloid neoplasms associated with Noonan syndrome
Myeloid neoplasms associated with Down syndromeb