Familial acute myeloid leukemia with mutated CEBPA is one form of a cancer of the blood-forming tissue (bone marrow) called acute myeloid leukemia. In normal bone marrow, early blood cells called hematopoietic stem cells develop into several types of blood cells: white blood cells (leukocytes) that protect the body from infection; red blood cells (erythrocytes) that carry oxygen; and platelets (thrombocytes), which are involved in blood clotting. In acute myeloid leukemia, the bone marrow makes large numbers of abnormal, immature white blood cells called myeloid blasts. Instead of developing into normal white blood cells, the myeloid blasts develop into cancerous leukemia cells. The large number of abnormal cells in the bone marrow interferes with the production of functional white blood cells, red blood cells, and platelets.

People with familial acute myeloid leukemia with mutated CEBPA have a shortage of white blood cells (leukopenia), leading to increased susceptibility to infections. A low number of red blood cells (anemia) also occurs in this disorder, resulting in fatigue and weakness. Affected individuals also have a reduction in the amount of platelets (thrombocytopenia), which can result in easy bruising and abnormal bleeding. Other symptoms of familial acute myeloid leukemia with mutated CEBPA may include fever and weight loss.

While acute myeloid leukemia is generally a disease of older adults, familial acute myeloid leukemia with mutated CEBPA often begins earlier in life, and it has been reported to occur as early as age 4. Between 50 and 65 percent of affected individuals survive their disease, compared with 25 to 40 percent of those with other forms of acute myeloid leukemia. However, people with familial acute myeloid leukemia with mutated CEBPA have a higher risk of having a new primary occurrence of this disorder after successful treatment of the initial occurrence.

As its name suggests, familial acute myeloid leukemia with mutated CEBPA is caused by mutations in the CEBPA gene that are passed down within families. These inherited mutations are present throughout a person's life in virtually every cell in the body.

The CEBPA gene provides instructions for making a protein called CCAAT enhancer-binding protein alpha. This protein is a transcription factor, which means that it attaches (binds) to specific regions of DNA and helps control the activity of certain genes. It is believed to act as a tumor suppressor, helping to prevent cells from growing and dividing too rapidly or in an uncontrolled way.

CEBPA gene mutations that cause familial acute myeloid leukemia with mutated CEBPA result in a shorter version of CCAAT enhancer-binding protein alpha. This shorter version is produced from one copy of the CEBPA gene in each cell, and it is believed to interfere with the tumor suppressor function of the normal protein produced from the second copy of the gene. Absence of the tumor suppressor function of CCAAT enhancer-binding protein alpha is believed to disrupt the regulation of blood cell production in the bone marrow, leading to the uncontrolled production of abnormal cells that occurs in acute myeloid leukemia.

In addition to the inherited mutation in one copy of the CEBPA gene in each cell, most individuals with familial acute myeloid leukemia with mutated CEBPA also acquire a mutation in the second copy of the CEBPA gene. The additional mutation, which is called a somatic mutation, is found only in the leukemia cells and is not inherited. The somatic CEBPA gene mutations identified in leukemia cells generally decrease the DNA-binding ability of CCAAT enhancer-binding protein alpha. The effect of this second mutation on the development of acute myeloid leukemia is unclear.

Normal Function

The CEBPA gene provides instructions for making a protein called CCAAT enhancer-binding protein alpha. This protein is a transcription factor, which means that it attaches (binds) to specific regions of DNA and helps control the activity (expression) of certain genes. CCAAT enhancer-binding protein alpha is involved in the maturation (differentiation) of certain blood cells. It is also believed to act as a tumor suppressor, which means that it is involved in cellular mechanisms that help prevent the cells from growing and dividing too rapidly or in an uncontrolled way.

Health Conditions Related to Genetic Changes

Familial acute myeloid leukemia with mutated CEBPA

At least six mutations in the CEBPA gene have been identified in families with familial acute myeloid leukemia with mutated CEBPA, which is a form of a blood cancer known as acute myeloid leukemia. These inherited mutations are present throughout a person's life in virtually every cell in the body. The mutations result in a shorter version of CCAAT enhancer-binding protein alpha. This shortened protein is produced from one copy of the CEBPA gene in each cell, and it is believed to interfere with the tumor suppressor function of the normal protein produced from the second copy of the gene. Absence of the tumor suppressor function of CCAAT enhancer-binding protein alpha is believed to disrupt the regulation of blood cell production, leading to the uncontrolled production of abnormal cells that occurs in acute myeloid leukemia.

In addition to the inherited mutation in one copy of the CEBPA gene in each cell, most individuals with familial acute myeloid leukemia with mutated CEBPA also acquire a mutation in the second copy of the CEBPA gene. The additional mutation, which is called a somatic mutation, is found only in the cancerous leukemia cells and is not inherited. The somatic CEBPA gene mutations that have been identified in leukemia cells generally decrease the DNA-binding ability of CCAAT enhancer-binding protein alpha. Researchers suggest that this second mutation may affect the normal differentiation of blood cells, although exactly how the mutation is involved in the development of acute myeloid leukemia is unclear.

Cytogenetically normal acute myeloid leukemia

Mutations in the CEBPA gene have been identified in some people with a form of acute myeloid leukemia known as cytogenetically normal acute myeloid leukemia (CN-AML). While large chromosomal abnormalities can be involved in the development of acute myeloid leukemia, about half of cases do not have these abnormalities; these are classified as CN-AML. Mutations in this gene are found in approximately 18 percent of individuals with CN-AML. When associated with CEBPA gene mutations, this condition can be inherited, in which case it is called familial acute myeloid leukemia with mutated CEBPA (described above), or not inherited (sporadic acute myeloid leukemia with mutated CEBPA).

Two types of CEBPA gene mutations can occur in both the inherited and non-inherited forms of CN-AML. One type leads to production of an abnormally short protein that interferes with the tumor suppressor function of normal versions of CCAAT enhancer-binding protein alpha. The other type of mutation blocks the DNA-binding ability of CCAAT enhancer-binding protein alpha. Impaired DNA binding interferes with the protein's ability to regulate gene expression and impairs its tumor suppressor function. Impairment of the tumor suppressor function of CCAAT enhancer-binding protein alpha leads to the uncontrolled production of abnormal white blood cells that occurs in acute myeloid leukemia.

Between 50 and 75 percent of all individuals who have acute myeloid leukemia with mutations in the CEBPA gene, both sporadic and familial, have two mutated CEBPA genes in each leukemia cell. The rest have only one CEBPA gene mutation. In the sporadic cases the mutation appears only in the leukemia cells, and in the familial cases it is present throughout the body. Somatic mutations in other genes can also contribute to the development of CN-AML.

Other Names for This Gene

• c/EBP alpha
• C/EBP-alpha
• CCAAT/enhancer binding protein (C/EBP), alpha
• CCAAT/enhancer binding protein alpha
• CCAAT/enhancer-binding protein alpha
• CEBP
• CEBPA_HUMAN

Genomic Location

Familial acute myeloid leukemia with mutated CEBPA is inherited in an autosomal dominant pattern. Autosomal dominant inheritance means that one copy of the altered CEBPA gene in each cell is sufficient to cause the disorder. Most affected individuals also acquire a second, somatic CEBPA gene mutation in their leukemia cells.

Acute myeloid leukemia occurs in approximately 3.5 in 100,000 individuals per year. Familial acute myeloid leukemia with mutated CEBPA is a very rare form of acute myeloid leukemia; only a few affected families have been identified.