STAT5b is rarer and described in more technical terms so revising. Hope many get something from this …. STAT3 mutations in Large Granular Lymphocyte Leukemia (T-cell type abbreviated as LGLL and NK as CLPD-NK).
We have thousands of genes that makeup our genetic material. They are inherited, but some can change or be modified over time by many factors – faulty duplication, infections, environmental toxins, for example. This change to a gene is called a genetic variant. The most prevalent acquired mutation or variant in our leukemia is STAT3. In T-cell LGL leukemia it was found nearly half had this genetic modification, acquired over time – not one we were born with. This means we don’t pass it on to our offspring.
What does it do?
STAT3 is present in humans and drives many pathways in the cell. Its presence is beneficial to life; however, when it becomes mutated or changed, it is associated with solid tumors, and especially prominent in blood cancer (CLL, AML, PV, ALL, MM, lymphomas and ours)1Chronic lymphocytic leukemia, Acute myelocytic leukemia, Polycythemia Vera, Acute lymphocytic leukemia, Multiple Myeloma. Here the mutation in our LGL cells causes an overdrive of cellular activities (this is called a gain of function or GOF) and results in a resistance to cell death or self-destruction. Cells in our immune system are programmed to fight “enemies,” do their jobs, and then retire or die. With a STAT3 mutation, these LGL cells keep on fighting and never give up! This results in small proteins or chemicals (think blow torches) being emitted even after the enemy has departed or been defeated. This leads to unintended consequences and results in attacks on our own tissue- contributing to the autoimmune part of our disease. This overactivity is the reason we are treated with IMMUNOSUPPRESSANTS! In the medical literature, it has been proposed this process or gain of function (GOF) occurs even in many without this mutation. When the Stat3 mutation is present, GOF acts in an even more charged state. Such patients often display more neutropenia and may have a more complicated course; ie, more symptomatic disease and more treatment options.
What are these Stat3 mutations and do they have relevance to the course of our disease?
STAT3 mutations are found in both T-cell LGLL and NK (CLPD-NK) forms of our disease. Some estimate they occur in 1/3 of patients in each type; others give a higher number to T-cell LGLL. Patients with RA (rheumatoid arthritis) and T-cell LGL leukemia have been frequently found to house Stat3 mutations.
The most common STAT3 mutation is Y640F; research found its presence is predictive of a good response to the drug Methotrexate. The next most common mutation is D661Y. No treatment has been linked as advantageous with this variant.
Researchers are vigorously investigating this topic and hope to find medications to tamp down STAT3 over-activity. There are a few clinical trials currently happening to address this issue.
Are there other effects from STAT3 mutations?
STAT3 mutations may distinguish truly malignant diseases with lymphocyte proliferation involving T cells and NK cells from transient and reactive expansions. It can aid in the diagnosis in perplexing cases.
Possibly the absence or presence of these mutations will explain the great variability we see in this disease and shed light on the variety of autoimmune disorders often associated with our leukemia. It has been stated “Abnormal STAT3 activity prevents normal control of the immune system, leading to autoimmunity.”
Here is a good explanation of the role “normal” (not mutated) STAT3 plays in our lives: “Through its regulation of gene activity, the STAT3 protein is involved in many cellular functions. It helps control cell growth and division (proliferation), cell movement (migration), and the self-destruction of cells (apoptosis). The STAT3 protein is active in tissues throughout the body. It plays an important role in the development and function of several body systems and is essential for life. In the immune system, the STAT3 protein transmits signals for the maturation of immune system cells, especially T cells and B cells. These cells help control the body’s response to foreign invaders such as bacteria and fungi. In addition, the protein is involved in the regulation of inflammation, which is one way the immune system responds to infection or injury, and it plays a role in cellular processes that promote allergic reactions (allergies). In the skeletal system, the STAT3 protein is involved in the formation of specialized cells that build and break down bone tissue. These cells are necessary for the normal development and maintenance