By Lauren Thayer from In The Cloud Copy
Systemic mastocytosis (SM) is a complicated condition of the blood in which excessive numbers of mast cells (a type of white blood cell) are present in the individual’s body. Mast cells normally function by releasing substances like histamine and leukotrienes to protect you from diseases and assist in healing of wounds. Extra mast cells can gather in different parts of the body and lead to a variety of symptoms such as itchy skin, rapid heart rate, lightheadedness, and more. While there is no treatment, managing the condition is possible. Recent developments in molecular characterization have the potential to aid in diagnosis and management of patients with SM.
There are five recognized types of SM, indolent SM (ISM), smoldering SM (SSM), SM with an associated clonal hematopoietic non-MC disease (MC-AHN), aggressive SM (ASM), and MC leukemia (MCL). Diagnosing SM is complicated, so the prevalence is likely grossly underestimated. One major and one minor criterion or three minor criteria must be found, in order to make a diagnosis.
The proliferation of mast cells happens when the stem cell factor binds to the extracellular domain of the KIT receptor. In SM, this happens at an uncontrolled rate, leading to mast cell infiltration to organs.
KIT Mutations
Mast cells express the KIT receptor which ultimately is responsible for development, proliferation, maturation, survival and mediator release from mast cells. Mast cells are usually regulated by availability of the KIT ligand stem cell factor (SCF), but when the gain-of-function receptor is present, there is uncontrolled cell proliferation which can lead to autonomous growth of mast cells, ultimately contributing to the disease. There have been documented instances of abnormal kinase activity of the KIT in systemic mastocytosis, as well as other malignancies, such as germ cell tumors and AML.
The mutations primarily seen are in the activation loop or the juxtamembrane domain (JMD). It is important to know where the mutation occurs, as therapies can differ. For example, tyrosine kinase inhibitors can be effective in the JMD mutation, but not the activation loop mutation.
Other gene mutations besides KIT have been seen in patients (up to 60%) with advanced SM. Many patients with SM-AHN are documented as having other gene mutations, while very few SSM and ISM patients have documented additional mutations. What these other mutations mean exactly, are still being investigated.
Diagnostic Considerations with KIT Mutations
When systemic mastocytosis is suspected, bone marrow cells are collected and a mutation analysis is performed, looking specifically for KIT mutations. The D816V mutation is seen in approximately 80% of SM patients, and therefore is used for standard testing and diagnosis. Being able to accurately identify this mutation will allow for more specific diagnosis and targeted treatment options.
Advancements in gene mutation analysis allows researchers and clinicians to classify three subgroups: (1) patients with MC-restricted KIT D816V; (2) patients with multilineage KIT D816V-involvement; and (3) patients with multi-mutated disease. Further classifying patients in these ways allows clinicians and researchers to target treatments that work for or against these patients, ultimately leading to better patient outcomes.
To learn more about this research, click here.
