The MDS Beacon™

A recent French study identifies the gene sequence TET2 as a potential cause of myelodysplastic syndrome (MDS), myeloproliferative diseases, and other blood cell developmental disorders.

TET2 is located on chromosome 4q24 and codes for proteins of unknown function. This study suggests their possible role in cell transformation, specifically in the early development of stem cells that become different blood types in a process called hematopoiesis.

In this study, researchers hypothesized that mutations in early hematopoietic stem cells were a common denominator to MDS, myeloproliferative disorders, and Acute Myeloid Leukemia (AML), a type of blood cancer. One third of MDS cases progress to AML, while defective development of white blood cells in the bone marrow cause myeloproliferative diseases.

The study found deletions and mutations in the TET2 gene sequence in approximately 15 percent of the study’s participants. This included 15 out of 81 patients with MDS (19 percent), 24 out of 198 with myeloproliferative disorders (24 percent), five out 21 with chronic myelomonocytic leukemia (12 percent), and two out of nine with AML (24 percent). These mutations are predicted to shorten the length of the encoded protein, causing partial or total loss of its yet unknown function.

Dr. Olivier Bernard, a senior author of the study, said, “Until now, very little was known regarding the molecular bases of some of [the myeloid malignancies in humans], such as myelodysplastic syndrome, and this study has shown that there are common genetic abnormalities among these malignant disorders.”

Myeloproliferative disorders have already been associated with a mutation in the gene sequence JAK2 V617F, which causes uncontrollable production of a certain protein. Analyses revealed that TET2 mutations occur independently of JAK2 V617F mutations.

In addition, study of the different MDS subtypes suggested that early cells retain the mutation as the disease progresses. TET2 mutations were observed to be more prevalent in developed, mature cells than in cells that still have the capability of becoming many different cell types. This is evidence that the mutation is important in early stages of hematopoiesis and affects future development.

The discovery of a specific gene sequence abnormality highly correlated with myeloid diseases is significant for earlier prediction and diagnoses.

More research will be done to specify mechanisms that influence the blood-related stem cells, as well as establish biological and clinical phenotypes that characterize the TET2 defects.

For more information, see the full text of the article at the New England Journal of Medicine.