2.1 Chronic myeloid leukemia

A genetic rearrangement (translocation) involving the ABL1 gene causes a type of cancer of blood-forming cells called chronic myeloid leukemia. This slow-growing cancer leads to an overproduction of abnormal white blood cells. Common features of the condition include excessive tiredness (fatigue), fever, weight loss, and an enlarged spleen.

The translocation involved in this condition, written as t(9;22), fuses part of the ABL1 gene from chromosome 9 with part of the BCR gene from chromosome 22, creating an abnormal fusion gene called BCR-ABL1. The abnormal chromosome 22, containing a piece of chromosome 9 and the BCR-ABL1 fusion gene, is commonly called the Philadelphia chromosome. The translocation is acquired during a person's lifetime and is present only in the abnormal blood cells. This type of genetic change, called a somatic mutation, is not inherited.

The protein produced from the abnormal fusion gene, called BCR-ABL1, functions as a kinase. However, unlike the ABL1 kinase, it does not require signals in the cell to turn it on. The constantly active BCR-ABL1 protein signals cells to continue dividing abnormally and prevents them from self-destructing, which leads to overproduction of the abnormal cells.

The presence of the Philadelphia chromosome provides a target for molecular therapies.

2.2 Other cancers

The BCR-ABL1 fusion gene (described above) is also involved in fast-growing blood cell cancers called acute leukemias. It has been found in 5 percent of children and up to 30 percent of adults with B-cell acute lymphoblastic leukemia and very rarely in acute myeloid leukemia. As in chronic myeloid leukemia, the BCR-ABL1 protein stimulates overproduction of abnormal white blood cells, leading to cancer. It is likely that the form of blood cancer that develops is influenced by the type of blood cell that acquires the mutation and other genetic changes that occur.

Rarely, translocations that lead to fusion of the ABL1 gene with genes other than BCR are associated with acute leukemias. For example, the ETV6-ABL1 fusion gene has been found in a small number of cases of B-cell acute lymphoid leukemia, and a chronic leukemia that can resemble chronic myeloid leukemia. The exact mechanisms by which these rare fusion genes lead to blood cancer are not completely understood, although it is likely that the proteins produced from them promote uncontrolled growth of cells.