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A Primer on Genetics: Mutations and STAT Proteins in LGL Leukemia

Thomas P. Loughran Jr., MD
The lab of Thomas Loughran, MD, and others around the world have been looking at how STAT proteins affect LGL leukemia.

If you’re familiarizing yourself with large granular lymphocyte (LGL) leukemia, you’ve probably come across information about DNA mutations and STAT proteins. About 30 to 40 percent of people with LGL leukemia have a STAT3 mutation, and about 2 percent have a STAT5b mutation, causing STAT proteins to malfunction.

Multiple studies have indicated that almost all people with LGL leukemia have a problem with STAT signaling, with or without a genetic mutation. The lab of Thomas Loughran, MD, and others around the world have been looking at how STAT proteins affect LGL leukemia. But what does this mean? What are STAT proteins and how do they relate to LGL leukemia?

A Brief Review of Genetics

For most people, grade-school lessons on DNA are long forgotten, so let’s briefly review. Within each cell of your body there’s DNA, which is basically a large set of instructions. Different cell types use parts of the DNA that tell those cells how to function; that’s called gene expression. When a gene gets expressed within a cell, RNA is produced in a process called transcription. Transcribing RNA is like copying the instructions from DNA. RNA is used to generate amino acid sequences that are the building blocks of proteins, as researchers at UVA have laid out here. STAT proteins are a product of this process, and their job is to facilitate the transcription of other genes.

If the DNA has a mistake (or mutation), then that mistake gets carried throughout the process. That means the final protein may not work the way it’s supposed to in your body. That’s what happens to a STAT protein within LGL leukemia cells, and then it doesn’t perform its function properly. Some cases where STAT proteins malfunction in LGL patients are a result of a mistake (mutation) in the DNA as described above. In other cases the function of the STAT protein is not regulated properly. This can occur from too much signaling coming into the cell, which makes the STAT protein perform its function for longer than it should.

What Is a STAT Protein’s Function?

When you get sick, your immune system starts working, and your immune cells create a type of protein called cytokines. These proteins may cause inflammation or suppress inflammation, and they help immune cells to fight off the invaders in your body.

Many cells have specific cytokine signaling pathways that tell them when to expand in response to infection and when to die off after they have done their intended job. The STAT proteins are part of signaling pathways that are often continually turned on in cancer. This is a problem because the cells do not die and continue being produced, and you end up with too many of them, as UVA research points out. In LGL leukemia, many people with the disease also have more inflammation-causing cytokines than someone without the disease. That can cause the symptoms associated with LGL leukemia and a host of other problems in your body.

What Does This Mean for LGL Leukemia Treatment?

Understanding what goes wrong in the body and pinpointing possible targets helps doctors and researchers develop treatment options. As researchers learn more about the relationship between mutations and STAT proteins and the development of LGL leukemia, they may be able to provide more targeted treatment options for the right people. Treatments that target cytokine-induced signaling through the STAT pathway may be able to help lessen the overproduction of harmful proteins and help cells die off appropriately.

With only about 1,000 people a year facing this diagnosis, research into LGL leukemia is limited. The more UVA is able to understand the disease by studying blood and tissue samples from those with it, the more options researchers and doctors can uncover to manage symptoms and help people resume a normal life.

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