<unk>  most often develops without an identifiable cause. Risk factors include exposure to an agent known to cause DNA damage, such as radiation, benzene, and certain chemotherapies; other risk factors have been inconsistently reported. Proving a connection between a suspected exposure and the development of<unk>  can be difficult, but the presence of genetic abnormalities may provide some supportive information. Secondary<unk>  can occur as a late toxicity of cancer therapy (therapy associated<unk> , t-MDS).<unk>  after exposure to radiation or alkylating agents such as busulfan, nitrosourea, or procarbazine, typically occurs 3–7 years after exposure and frequently demonstrates loss of chromosome 5 or 7.<unk>  after exposure to DNA topoisomerase II inhibitors occurs after a shorter latency of only 1–3 years and can have a 11q23 translocation. Other pre-existing bone-marrow disorders such as acquired aplastic anemia following immunosuppressive treatment and Fanconi anemia can evolve into<unk> .<unk>  is thought to arise from mutations in the multipotent bone-marrow stem cell, but the specific defects responsible for these diseases remain poorly understood. Differentiation of blood precursor cells is impaired, and a significant increase in levels of apoptotic cell death occurs in bone-marrow cells. Clonal expansion of the abnormal cells results in the production of cells that have lost the ability to differentiate. If the overall percentage of bone-marrow myeloblasts rises over a particular cutoff (20% for WHO and 30% for FAB), then transformation to acute myelogenous leukemia (AML) is said to have occurred. The progression of<unk>  to AML is a good example of the multistep theory of carcinogenesis in which a series of mutations occur in an initially normal cell and transforms it into a cancer cell. While recognition of leukemic transformation was historically important (see History), a significant proportion of the morbidity and mortality attributable to<unk>  results not from transformation to AML, but rather from the cytopenias seen in all<unk>  patients. While anemia is the most common cytopenia in<unk>  patients, given the ready availability of blood transfusion,<unk>  patients rarely suffer injury from severe anemia. The two most serious complications in<unk>  patients resulting from their cytopenias are bleeding (due to lack of platelets) or infection (due to lack of white blood cells). Long-term transfusion of packed red blood cells leads to iron overload. Genetics The recognition of epigenetic changes in DNA structure in<unk>  has explained the success of two (namely the hypomethylating agents 5-azacytidine and decitabine) of three (the third is lenalidomide) commercially available medications approved by the U.S. Food and Drug Administration to treat<unk> . Proper DNA methylation is critical in the regulation of proliferation genes, and the loss of DNA methylation control can lead to uncontrolled cell growth and cytopenias. The recently approved DNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly DNA methylation profile in the hematopoietic stem cell nucleus, thereby restoring normal blood counts and retarding the progression of<unk>  to acute leukemia. Some authors have proposed that the loss of mitochondrial function over time leads to the accumulation of DNA mutations in hematopoietic stem cells, and this accounts for the increased incidence of<unk>  in older patients. Researchers point to the accumulation of mitochondrial iron deposits in the ringed sideroblast as evidence of mitochondrial dysfunction in<unk> . 5q-<unk>  Since at least 1974, the deletion in the long arm of chromosome 5 has been known to be associated with dysplastic abnormalities of hematopoietic stem cells. By 2005, lenalidomide, a chemotherapy drug, was recognized to be effective in<unk>  patients with the 5q-<unk> , and in December 2005, the US FDA approved the drug for this indication. Patients with isolated 5q-, low IPSS risk, and transfusion dependence respond best to lenalidomide. Typically, prognosis for these patients is favorable, with a 63-month median survival. Lenalidomide has dual action, by lowering the malignant clone number in patients with 5q-, and by inducing better differentiation of healthy erythroid cells, as seen in patients without 5q deletion. Splicing factor mutations Mutations in splicing factors have been found in 40–80% of cases with<unk> , particularly in those with ringed sideroblasts. IDH1 and IDH2 mutations Mutations in the genes encoding for isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) occur in 10–20% of patients with<unk> , and confer a worsened prognosis in low-risk<unk> . Because the incidence of IDH1/2 mutations increases as the disease malignancy increases, these findings together suggest that IDH1/2 mutations are important drivers of progression of<unk>  to a more malignant disease state. GATA2 deficiency GATA2 deficiency is a group of disorders caused by a defect, familial, or sporadic inactivating mutations, in one of the two GATA2 genes. These autosomal dominant mutations cause a reduction, in the cellular levels of the gene's product, GATA2. The GATA2 protein is a transcription factor critical for the embryonic development, maintenance, and functionality of blood-forming, lymph-forming, and other tissue-forming stem cells. In consequence of these mutations, cellular levels of GATA2 are low and individuals develop over time hematological, immunological, lymphatic, or other presentations. Prominent among these presentations is<unk>  that often progresses to acute myelocytic leukemia or less commonly chronic myelomonocytic leukemia. Transient myeloproliferative disease Transient myeloproliferative disease is the abnormal proliferation of a clone of noncancerous megakaryoblasts in the liver and bone marrow. The disease is restricted to individuals with Down<unk>  or genetic changes similar to those in Down<unk> , develops during pregnancy or shortly after birth, and resolves within 3 months, or in about 10% of cases, progresses to acute megakaryoblastic leukemia.
Myelodysplastic syndrome
Primary myelofibrosis
Acute myeloid leukemia
Myeloid leukemia
Autoimmune neutropenia
Mixed-phenotype acute leukemia
Childhood leukemia
B-cell leukemia