2.1 PDGFRB-Associated Chronic Eosinophilic Leukemia

PDGFRB-associated chronic eosinophilic leukemia, a type of cancer of blood-forming cells, can be caused by a genetic rearrangement known as a translocation that brings together part of the ETV6 gene and part of another gene called PDGFRB, creating the ETV6-PDGFRB fusion gene. The translocation that leads to the ETV6-PDGFRB fusion gene is a somatic mutation, which is acquired during a person's lifetime and occurs initially in a single cell. This cell continues to grow and divide, producing a group of cells with the same mutation (a clonal population).

The protein produced from the ETV6-PDGFRB fusion gene, called ETV6/PDGFRβ, functions differently than the proteins normally produced from the individual genes. Unlike the normal PDGFRβ protein, the fusion protein is always active, which means certain cell signaling pathways are constantly turned on. The fusion protein is unable to repress gene activity regulated by the normal ETV6 protein, so gene activity is increased. The overactive signaling pathways and abnormal gene activity increase the proliferation and survival of cells. When the ETV6-PDGFRB fusion gene mutation occurs in cells that develop into blood cells, the growth of white blood cells called eosinophils (and occasionally other white blood cells, such as neutrophils and mast cells) is poorly controlled, leading to PDGFRB-associated chronic eosinophilic leukemia. It is unclear why eosinophils are preferentially affected by this genetic change.

2.2 Other Cancers

Translocations involving the ETV6 gene and more than 30 other genes have been found to cause different types of leukemia, including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), and a bone marrow disease called myelodysplastic syndrome (MDS). Depending on the gene fused with ETV6, a number of mechanisms can cause these conditions, such as impaired regulation of gene activity, abnormal signaling, or loss of normal gene function. The ETV6 gene translocations that cause these diseases are somatic mutations and are not inherited.