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.