Systemic mastocytosis (SM), is a rare blood disorder that is characterized by the over-proliferation of mast cells caused by a gain-of-function mutations in KIT, a receptor tyrosine kinase. The most common mutation in KIT is D816V, which causes ligand-independent activation of the receptor. Inhibitors of KIT-D816V can be highly effective in reducing mast cell proliferation, but some patients develop drug resistance. Drug resistance and poor prognosis of patients with SM is associated with mutations in additional genes such as RUNX1, a transcription factor important for the formation and maturation of blood cells. We hypothesize that RUNX1 mutations may confer resistance to drugs targeting mutant KIT. To test this hypothesis, we used the Lenti-X CRISPR/Cas9 system on a human systemic mastocytosis cell line (HMC-1.2) to introduce a RUNX1 truncating mutation commonly observed in patients with SM.