Previously unknown genetic mutations have been found in cases of well-differentiated systemic mastocytosis (WDSM), a rare SM variant, according to a recently published study in The Journal of Allergy and Clinical Immunology.
WDSM is a rare form of mastocytosis that affects less than 2% of patients with the disease. The variant is characterized by normal-looking mast cells under the microscope, meaning that they are round and enlarged instead of irregularly shaped as is typically seen in SM, which makes diagnosis more challenging. WDSM can occur with any SM subtype.
Most cases of SM are caused by a mutation in the KIT gene, which codes for the KIT receptor involved in mast cell activation. The most common mutation, a change called p.D816V, creates a state of constant KIT receptor activation. In WDSM, the p.D816V mutation is frequently absent, which makes diagnosis even more difficult.
What is a KIT gene mutation?
SM is usually caused by a sporadic mutation in the KIT gene, which codes for a protein called CD117 transmembrane tyrosine kinase. The protein is involved in the growth, survival and migration of mast cells. The most common KIT mutation associated with SM is the D816V mutation, which results in the amino acid aspartic acid being replaced by the amino acid valine in the protein chain.
To better understand the genetic characteristics of WDSM, the authors analyzed samples from 454 patients with systemic mastocytosis from two major cohorts. They found seven cases of WDSM, none of whom had the common p.D816V mutation. However, six had rare germline KIT mutations, two of which had not been previously identified in other patients.
Further examination showed these mutations made KIT more responsive to signaling but not permanently active. This places them in the class I mutation group, which needs a trigger to activate; “class II” mutations like p.D816V, on the other hand, are always active.
Additionally, the authors observed that WDSM mast cells often had abnormal proteins (CD2 and CD25) inside the cell, rather than on their surface. This means that common tests that look for these proteins may miss the diagnosis, highlighting the need for specific tissue staining methods.
Read more about SM testing and diagnosis
This research increases the number of known KIT mutations causing WDSM and shows that different testing methods are essential for accurate diagnosis.
“Future studies should determine whether specific TKI(s), anti-KIT antibodies, and/or anti-KIT toxin conjugates might effectively reduce KIT autophosphorylation36 450 of each KIT variant 451 that underlies WDSM in order to identify personalized treatment strategies tailored to the specific 452 driving mutation,” the authors concluded.
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