What are the genetic changes related to PDGFRA-associated chronic eosinophilic leukemia ?
PDGFRA-associated chronic eosinophilic leukemia is caused by mutations in the PDGFRA gene. This condition usually occurs as a result of genetic rearrangements that fuse part of the PDGFRA gene with part of another gene. Rarely, changes in single DNA building blocks (point mutations) in the PDGFRA gene are found in people with this condition. Genetic rearrangements and point mutations affecting the PDGFRA gene are somatic mutations, which are mutations acquired during a person's lifetime that are present only in certain cells. The somatic mutation occurs initially in a single cell, which continues to grow and divide, producing a group of cells with the same mutation (a clonal population).  The most common genetic abnormality in PDGFRA-associated chronic eosinophilic leukemia results from a deletion of genetic material from chromosome 4, which brings together part of the PDGFRA gene and part of the FIP1L1 gene, creating the FIP1L1-PDGFRA fusion gene.  The FIP1L1 gene provides instructions for a protein that plays a role in forming the genetic blueprints for making proteins (messenger RNA or mRNA).  The PDGFRA gene provides instructions for making a receptor protein that is found in the cell membrane of certain cell types. Receptor proteins have specific sites into which certain other proteins, called ligands, fit like keys into locks. When the ligand attaches (binds), the PDGFRA receptor protein is turned on (activated), which leads to activation of a series of proteins in multiple signaling pathways. These signaling pathways control many important cellular processes, such as cell growth and division (proliferation) and cell survival.  The FIP1L1-PDGFRA fusion gene (as well as other PDGFRA fusion genes) provides instructions for making a fusion protein that has the function of the normal PDGFRA protein. However, the fusion protein does not require ligand binding to be activated. Similarly, point mutations in the PDGFRA gene can result in a PDGFRA protein that is activated without ligand binding. As a result, the signaling pathways are constantly turned on (constitutively activated), which increases the proliferation and survival of cells. When the FIP1L1-PDGFRA fusion gene mutation or point mutations in the PDGFRA gene occur in blood cell precursors, the growth of eosinophils (and occasionally other blood cells, such as neutrophils and mast cells) is poorly controlled, leading to PDGFRA-associated chronic eosinophilic leukemia. It is unclear why eosinophils are preferentially affected by this genetic change.