Researchers have developed a new mouse model that carries the mouse equivalent of the genetic change behind most cases of systemic mastocytosis (SM). Described in a study published in the journal Leukemia, the model could give scientists a new tool to study SM and test potential treatments.
Earlier mouse models of SM mostly relied on inserting the human KIT D816V mutation into mice. According to the researchers, these models often took a long time to develop disease, affected only some of the animals, or produced features that differ from human SM.
Understanding KIT D816V and SM
More than 90% of people with SM carry a change in the KIT gene called D816V. KIT holds the instructions for a receptor on the mast cell surface. Normally, this receptor turns on only when a growth signal molecule attaches to it. The D816V mutation keeps the receptor switched on all the time, so mast cells keep receiving signals to grow, multiply and survive. Over time, these abnormal mast cells accumulate in the skin, bone marrow and other organs, causing the symptoms of SM.
In the new model, the team placed D814V, the mouse version of the mutation, directly into the animals’ own Kit gene, so the mutant receptor is made under the gene’s natural controls. The mice consistently developed a disease resembling SM with an associated hematologic neoplasm (SM-AHN), an advanced form of SM in which SM occurs alongside another blood cancer.
Within weeks, these mastocytosisMastocytosis Rare disease caused by the buildup of mast cells. Cutaneous mastocytosis primarily affects the skin and is more common in children, while systemic mastocytosis affects internal organs and is more common in adults.-mutant mouse models developed mast cellMast cell A type of white blood cell produced in the bone marrow. They help defend against infections and play a key role in allergic reactions. In SM, mast cells become overactive and build up throughout the body. accumulation in the skin, stomach, spleen, liver and lungs. Blood levels of mast cell enzymes also rose. The mice had high white and red blood cell counts and greatly enlarged spleens and livers. They also died significantly sooner than mice without the mutation, living an average of 33 days after it was switched on.
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To test whether the mutant cells had a growth advantage, the researchers performed a competitive bone marrow transplant. They mixed equal amounts of bone marrow from affected and normal mice and transplanted it into mice whose own marrow had been cleared with radiation. The mutant cells outgrew the normal cells, making up more than 90% of bone marrow cells after 16 weeks, and the recipients developed the same disease.
Read more about KIT D816V: New ultra-sensitive KIT D816V test launched for systemic mastocytosis
In these mice, 16 days of avapritinib, an approved SM therapy that specifically targets mutant KIT, reduced the share of mutant cells and kept mast cell enzyme levels from rising. It also returned white blood cell counts to normal and shrank enlarged spleens. The therapy was also found to extend survival.
In laboratory tests, mast cells from mice carrying the mutation responded to much lower doses of avapritinib than mast cells from mice without it. Two investigational drugs that also target mutant KIT, elenestinib and bezuclastinib, showed the same pattern.
“Together, these data show that our mouse model responds to treatment with a clinically relevant inhibitor, specifically developed to target oncogenic KIT D816V in advanced SMAdvanced SM In these subtypes of SM, mast cells begin to damage organs. Advanced SM includes the subtypes aggressive SM, mast cell leukemia and SM with an associated hematological neoplasm. patients.”
According to the researchers, this might make the model useful for testing whether new drugs selectively block mutant KIT while sparing the normal protein.
