PDGFRB-associated chronic eosinophilic leukemia is a type of cancer of blood-forming cells. It is characterized by an elevated number of white blood cells called eosinophils in the blood. These cells help fight infections by certain parasites and are involved in the inflammation associated with allergic reactions. However, these circumstances do not account for the increased number of eosinophils in PDGFRB-associated chronic eosinophilic leukemia. Some people with this condition have an increased number of other types of white blood cells, such as neutrophils or mast cells, in addition to eosinophils. People with this condition can have an enlarged spleen (splenomegaly) or enlarged liver (hepatomegaly). Some affected individuals develop skin rashes, likely as a result of an abnormal immune response due to the increased number of eosinophils.

PDGFRB-associated chronic eosinophilic leukemia is caused by genetic rearrangements that join part of the PDGFRB gene with part of another gene. At least 20 genes have been found that fuse with the PDGFRB gene to cause PDGFRB-associated chronic eosinophilic leukemia. The most common genetic abnormality in this condition results from a rearrangement (translocation) of genetic material that brings part of the PDGFRB gene on chromosome 5 together with part of the ETV6 gene on chromosome 12, creating the ETV6-PDGFRB fusion gene.

The PDGFRB gene provides instructions for making a protein that plays a role in turning on (activating) signaling pathways that control many cell processes, including cell growth and division (proliferation). The ETV6 gene provides instructions for making a protein that turns off (represses) gene activity. This protein is important in development before birth and in regulating blood cell formation. The protein produced from the ETV6-PDGFRB fusion gene, called ETV6/PDGFRβ, functions differently than the proteins normally produced from the individual genes. Like the normal PDGFRβ protein, the ETV6/PDGFRβ fusion protein turns on signaling pathways. However, the fusion protein does not need to be turned on to be active, so the signaling pathways are constantly turned on (constitutively activated). The fusion protein is unable to repress gene activity regulated by the normal ETV6 protein, so gene activity is increased. The constitutively active signaling pathways and abnormal gene activity increase the proliferation and survival of cells.

When the ETV6-PDGFRB fusion gene variant (also known as a mutation) occurs in cells that develop into blood cells, the growth of eosinophils (and occasionally other 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.

Normal Function

The ETV6 gene provides instructions for producing a protein that functions as a transcription factor, which means that it attaches (binds) to specific regions of DNA and controls the activity of certain genes. The ETV6 protein is found in the nucleus of cells throughout the body, where it turns off (represses) gene activity. It plays a key role in development before birth and in regulating blood cell formation.

Health Conditions Related to Genetic Changes

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.

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.

Other Names for This Gene

• ETS translocation variant 6
• ets variant 6
• ets variant gene 6 (TEL oncogene)
• ETS-related protein Tel1
• ETV6_HUMAN
• TEL
• TEL1 oncogene
• transcription factor ETV6

Genomic Location

Normal Function

The PDGFRB gene provides instructions for making a protein called platelet-derived growth factor receptor beta (PDGFRβ), which is part of a family of proteins called receptor tyrosine kinases. Receptor tyrosine kinases transmit signals from the cell surface into the cell through a process called signal transduction. The PDGFRβ protein is found in the cell membrane of certain cell types, where a protein called platelet-derived growth factor attaches (binds) to it. This binding turns on (activates) the PDGFRβ protein, which then activates other proteins inside the cell by adding a cluster of oxygen and phosphorus atoms (a phosphate group) at specific positions. This process, called phosphorylation, leads to the activation of a series of proteins in multiple signaling pathways.

The signaling pathways stimulated by the PDGFRβ protein control many important processes in the cell such as growth and division (proliferation), movement, and survival. PDGFRβ protein signaling is important for the development of many types of cells throughout the body.

Health Conditions Related to Genetic Changes

PDGFRB-associated chronic eosinophilic leukemia

Genetic rearrangements (translocations) involving the PDGFRB gene cause a type of cancer of blood-forming cells called PDGFRB-associated chronic eosinophilic leukemia. This condition is characterized by an increased number of eosinophils, a type of white blood cell. The most common of these translocations brings together part of the PDGFRB gene with another gene called ETV6, whose function is to turn off gene activity. Together, these pieces create the ETV6-PDGFRB fusion gene. Occasionally, genes other than ETV6 are fused with the PDGFRB gene. The translocations that lead to these fusion genes are somatic mutations, which are acquired during a person's lifetime and occur 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 (as well as other PDGFRB fusion genes) functions differently than the proteins normally produced from the individual genes. The ETV6/PDGFRβ fusion protein does not require ligand binding to be activated and cannot bind to DNA to turn off gene activity. As a result, signaling pathways are constantly turned on (constitutively activated) and gene activity is increased, which increases the proliferation and survival of cells.

When the ETV6-PDGFRB fusion gene mutation occurs in cells that develop into blood cells, the growth of 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.

Primary familial brain calcification

At least six mutations in the PDGFRB gene have been found to cause primary familial brain calcification. This condition is characterized by abnormal deposits of calcium (calcification) in the brain, which can lead to movement and psychiatric problems. These mutations change single protein building blocks (amino acids) in the PDGFRβ protein. These changes impair the protein's signaling ability.

It is unclear how PDGFRB gene mutations cause primary familial brain calcification. The altered signaling may result in an abnormally large amount of calcium entering the cells that line blood vessels in the brain, leading to calcification of these blood vessels. Alternatively, changes in PDGFRB signaling could disrupt processes that regulate levels of phosphate and calcium in brain cells, leading to the formation of calcium deposits. In the brain, the excess phosphate combines with calcium and forms deposits.

The PDGFRB gene is active (expressed) throughout the body; it is unclear why the effects of these mutations are limited to structures deep within the brain that help start and control movement (basal ganglia) and to other brain regions that are involved in primary familial brain calcification.

Other disorders

Additional mutations in the PDGFRB gene cause a variety of disorders including infantile myofibromatosis; Kosaki overgrowth syndrome; and premature aging syndrome, Penttinen type.

Infantile myofibromatosis is a muscle disorder that causes the formation of multiple noncancerous (benign) tumors in the skin, muscles, or bones. These tumors are generally present at birth or in early infancy.

Kosaki overgrowth syndrome is characterized by above-average height and large hands and feet. Affected individuals have highly stretchy (elastic) and fragile skin. People with this condition also have distinctive facial features and brain abnormalities that result in intellectual disability and psychological problems.

Premature aging syndrome, Penttinen type is characterized by a lack of fatty tissue under the skin (lipoatrophy). This lack of fat, together with thin, wrinkled skin and veins visible beneath the skin, makes affected individuals look older than their biological age.

In all of these conditions, PDGFRB gene mutations result in increased cell signaling. While it is unclear how mutations in one gene can lead to so many different conditions, it is thought that particular mutations may affect different signaling pathways, leading to changes in specific body systems.

Other Names for This Gene

• beta-type platelet-derived growth factor receptor
• CD140 antigen-like family member B
• CD140B
• PDGF-R-beta
• PDGFR-1
• PDGFR-beta
• PDGFR1
• PGFRB_HUMAN
• platelet-derived growth factor receptor 1
• platelet-derived growth factor receptor beta
• platelet-derived growth factor receptor, beta polypeptide

Genomic Location

PDGFRB-associated chronic eosinophilic leukemia is not inherited and occurs in people with no history of the condition in their families. Chromosomal rearrangements that lead to a PDGFRB fusion gene are somatic variants, which are variants acquired during a person's lifetime and present only in certain cells. The somatic variant occurs initially in a single cell, which continues to grow and divide, producing a group of cells with the same variant (a clonal population).

The exact prevalence of PDGFRB-associated chronic eosinophilic leukemia is unknown. For unknown reasons, males are up to nine times more likely than females to develop PDGFRB-associated chronic eosinophilic leukemia.