acute myeloid leukemia acute myeloid leukemia acute myeloid leukemia (aml) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. symptoms may include feeling tired, shortness of breath, easy bruising and bleeding, and increased risk of infection. occasionally, spread may occur to the brain, skin, or gums. as an acute leukemia, aml progresses rapidly, and is typically fatal within weeks or months if left untreated. acute myeloid leukemiaother namesacute myelogenous leukemia, acute nonlymphocytic leukemia (anll), acute myeloblastic leukemia, acute granulocytic leukemiabone marrow aspirate showing acute myeloid leukemia, arrows indicate auer rodsspecialtyhematology, oncologysymptomsfeeling tired, shortness of breath, easy bruising and bleeding, increased risk of infectionusual onsetall ages, most frequently ~65–75 years oldrisk factorssmoking, previous chemotherapy or radiation therapy, myelodysplastic syndrome, benzenediagnostic methodbone marrow aspiration, blood testtreatmentchemotherapy, radiation therapy, stem cell transplantprognosisfive-year survival ~29% (us, 2017)frequency1 million (2015)deaths147,100 (2015) risk factors include smoking, previous chemotherapy or radiation therapy, myelodysplastic syndrome, and exposure to the chemical benzene. the underlying mechanism involves replacement of normal bone marrow with leukemia cells, which results in a drop in red blood cells, platelets, and normal white blood cells. diagnosis is generally based on bone marrow aspiration and specific blood tests. aml has several subtypes for which treatments and outcomes may vary. the first-line treatment of aml is usually chemotherapy, with the aim of inducing remission. people may then go on to receive additional chemotherapy, radiation therapy, or a stem cell transplant. the specific genetic mutations present within the cancer cells may guide therapy, as well as determine how long that person is likely to survive. in 2015, aml affected about one million people, and resulted in 147,000 deaths globally. it most commonly occurs in older adults. males are affected more often than females. the five-year survival rate is about 35% in people under 60 years old and 10% in people over 60 years old. older people whose health is too poor for intensive chemotherapy have a typical survival of five to ten months. it accounts for roughly 1.1% of all cancer cases, and 1.9% of cancer deaths in the united states. signs and symptoms swollen gums due to infiltration by leukemia cells in a person with aml most signs and symptoms of aml are caused by the crowding out in bone marrow of space for normal blood cells to develop. a lack of normal white blood cell production makes people more susceptible to infections. a low red blood cell count (anemia) can cause fatigue, paleness, shortness of breath and palpitations. a lack of platelets can lead to easy bruising, bleeding from the nose (epistaxis), small blood vessels on the skin (petechiae) or gums, or bleeding with minor trauma. other symptoms may include fever, fatigue worse than what can be attributed to anaemia alone, weight loss and loss of appetite. enlargement of the spleen may occur in aml, but it is typically mild and asymptomatic. lymph node swelling is rare in most types of aml, except for acute myelomonocytic leukemia (amml). the skin can be involved in the form of leukemia cutis; sweet's syndrome; or non-specific findings: flat lesions (macules), raised lesion papules, pyoderma gangrenosum and vasculitis. some people with aml may experience swelling of the gums because of infiltration of leukemic cells into the gum tissue. involvement of other parts of the body such as the gastrointestinal tract, respiratory tract and other parts is possible but less common. one area which has particular importance for treatment is whether there is involvement of the meninges around the central nervous system. risk factors most cases of aml do not have exposure to any identified risk factors. however, a number of risk factors for developing aml have been identified. these include other blood disorders, chemical exposures, ionizing radiation, and genetic risk factors. where a defined exposure to past chemotherapy, radiotherapy, toxin or hematologic malignancy is known, this is termed secondary aml. other blood disorders other blood disorders, particularly myelodysplastic syndrome (mds) and less commonly myeloproliferative neoplasms (mpn), can evolve into aml; the exact risk depends on the type of mds/mpn. the presence of asymptomatic clonal hematopoiesis also raises the risk of transformation into aml. chemical exposure exposure to anticancer chemotherapy, in particular alkylating agents, can increase the risk of subsequently developing aml. other chemotherapy agents, including fludarabine, and topoisomerase ii inhibitors are also associated with the development of aml; most commonly after 4–6 years and 1–3 years respectively. these are often associated with specific chromosomal abnormalities in the leukemic cells. other chemical exposures associated with the development of aml include benzene, chloramphenicol and phenylbutazone. radiation high amounts of ionizing radiation exposure, such as that used for radiotherapy used to treat some forms of cancer, can increase the risk of aml. people treated with ionizing radiation after treatment for prostate cancer, non-hodgkin lymphoma, lung cancer, and breast cancer have the highest chance of acquiring aml, but this increased risk returns to the background risk observed in the general population after 12 years. historically, survivors of the atomic bombings of hiroshima and nagasaki had an increased rate of aml, as did radiologists exposed to high levels of x-rays prior to the adoption of modern radiation safety practices. genetics most cases of aml arise spontaneously, however there are some genetic mutations associated with an increased risk. several congenital conditions increase the risk of leukemia; the most common is down syndrome, with other more rare conditions including fanconi anemia, bloom syndrome and ataxia-telangiectasia (all characterised by problems with dna repair), and kostmann syndrome. other factors being overweight and obese increase the risk of developing aml, as does any amount of active smoking. for reasons that may relate to substance or radiation exposure, certain occupations have a higher rate of aml; particularly work in the nuclear power industry, electronics or computer manufacturing, fishing and animal slaughtering and processing. pathophysiology diagram showing the cells where aml develops. the malignant cell in aml is the myeloblast. in normal development of blood cells (hematopoiesis), the myeloblast is an immature precursor of myeloid white blood cells; a normal myeloblast will mature into a white blood cell such as an eosinophil, basophil, neutrophil or monocyte. in aml, though, a single myeloblast accumulates genetic changes which stop maturation, increase its proliferation, and protect it from programmed cell death (apoptosis). much of the diversity and heterogeneity of aml is because leukemic transformation can occur at a number of different steps along the differentiation pathway. genetic abnormalities or the stage at which differentiation was halted form part of modern classification systems. specific cytogenetic abnormalities can be found in many people with aml; the types of chromosomal abnormalities often have prognostic significance. the chromosomal translocations encode abnormal fusion proteins, usually transcription factors whose altered properties may cause the "differentiation arrest". for example, in apl, the t(15;17) translocation produces a pml-rara fusion protein which binds to the retinoic acid receptor element in the promoters of several myeloid-specific genes and inhibits myeloid differentiation. the clinical signs and symptoms of aml result from the growth of leukemic clone cells, which tends to interfere with the development of normal blood cells in the bone marrow. this leads to neutropenia, anemia, and thrombocytopenia. other symptoms can arise from the infiltration of malignant cells into parts of the body, such as the gingiva and skin. many cells develop mutations in genes that affect epigenetics, such as dna methylation. when these mutations occur, it is likely in the early stages of aml. such mutations include in the dna demethylase tet2 and the metabolic enzymes idh1 and idh2, which lead to the generation of a novel oncometabolite, d-2-hydroxyglutarate, which inhibits the activity of epigenetic enzymes such as tet2. epigenetic mutations may lead to the silencing of tumor suppressor genes and/or the activation of proto-oncogenes. diagnosis bone marrow: myeloblasts with auer rods seen in aml a complete blood count, which is a blood test, is one of the initial steps in the diagnosis of aml. it may reveal both an excess of white blood cells (leukocytosis) or a decrease (leukopenia), and a low red blood cell count (anemia) and low platelets (thrombocytopenia) can also be commonly seen. a blood film may show leukemic blast cells. inclusions within the cells called auer rods, when seen, make the diagnosis highly likely. a definitive diagnosis requires a bone marrow aspiration and biopsy. bone marrow is examined under light microscopy, as well as flow cytometry, to diagnose the presence of leukemia, to differentiate aml from other types of leukemia (e.g. acute lymphoblastic leukemia), and to provide information about how mature or immature the affected cells are that can assist in classifying the subtype of disease. a sample of marrow or blood is typically also tested for chromosomal abnormalities by routine cytogenetics or fluorescent in situ hybridization. genetic studies may also be performed to look for specific mutations in genes such as flt3, nucleophosmin, and kit, which may influence the outcome of the disease. cytochemical stains on blood and bone marrow smears are helpful in the distinction of aml from all, and in subclassification of aml. the combination of a myeloperoxidase or sudan black stain and a nonspecific esterase stain will provide the desired information in most cases. the myeloperoxidase or sudan black reactions are most useful in establishing the identity of aml and distinguishing it from all. the nonspecific esterase stain is used to identify a monocytic component in amls and to distinguish a poorly differentiated monoblastic leukemia from all. the standard classification scheme for aml is the world health organization (who) system. according to the who criteria, the diagnosis of aml is established by demonstrating involvement of more than 20% of the blood and/or bone marrow by leukemic myeloblasts, except in three forms of acute myeloid leukemia with recurrent genetic abnormalities: t(8;21), inv(16) or t(16;16), and acute promyelocytic leukemia with pml-rara, in which the presence of the genetic abnormality is diagnostic irrespective of blast percent. myeloid sarcoma is also considered a subtype of aml independently of the blast count. the older french-american-british (fab) classification, which is no longer widely used, is a bit more stringent, requiring a blast percentage of at least 30% in bone marrow or peripheral blood for the diagnosis of aml. because acute promyelocytic leukemia has the highest curability and requires a unique form of treatment, it is important to quickly establish or exclude the diagnosis of this subtype of leukemia. fluorescent in situ hybridization performed on blood or bone marrow is often used for this purpose, as it readily identifies the chromosomal translocation that characterizes apl. there is also a need to molecularly detect the presence of pml/rara fusion protein, which is an oncogenic product of that translocation. world health organization the who classification of aml attempts to be more clinically useful and to produce more meaningful prognostic information than the fab criteria. each of the who categories contains numerous descriptive subcategories of interest to the hematopathologist and oncologist; however, most of the clinically significant information in the who schema is communicated via categorization into one of the subtypes listed below. the revised fourth edition of the who classification of tumours of haematopoietic and lymphoid tissues was released in 2016. this classification, which is based on a combination of genetic and immunophenotypic markers and morphology, defines the subtypes of aml and related neoplasms as: in 2022 a new classification has been published. name description icd-o acute myeloid leukemia with recurrent genetic abnormalities includes: aml with translocations between chromosome 8 and 21 – runx1-runx1t1; (icd-o 9896/3); aml with inversions in chromosome 16 – or internal translocations in it – cbfb-myh11; (icd-o 9871/3); acute promyelocytic leukemia with pml-rara; (icd-o 9866/3); aml with translocations between chromosome 9 and 11 – kmt2a-mllt3; aml with translocations between chromosome 6 and 9 – dek-nup214; aml with inversions in chromosome 3 – or internal translocations in it – gata2, mecom megakaryoblastic aml with translocations between chromosome 1 and 22 – rbm15-mkl1; aml with mutated npm1 aml with biallelic mutations of cebpa provisional: aml with bcr-abl1 and aml with mutated runx1 multiple aml with myelodysplasia-related changes this category includes people who have had a prior documented myelodysplastic syndrome (mds) or myeloproliferative disease (mpd) that then has transformed into aml; who have cytogenetic abnormalities characteristic