IN-VIVO DIFFERENTIATION OF MAST-CELLS FROM ACUTE MYELOID-LEUKEMIA BLASTS CARRYING A NOVEL ACTIVATING LIGAND-INDEPENDENT C-KIT MUTATION

The primary role of protooncogene c-kit in mast cell differentiation i s supported by the development of mast cells from CD34(+)/CD117(+) (c- kit) myeloid precursors. Growth factor independence, neoplastic transf ormation and differentiation of mast cells were found in association w ith c-kit activating mutations in both murine and human mastocytoma an d mast cell diseases. We have identified a novel c-kit mutation (DX16Y ) in peripheral blood mononuclear cells from a patient with AML (MZ), massive presence of mast cells in bone marrow and rapid progression of the disease. The mutation, a G-->T transversion at nt 2467 of the c-k it gene resulting in Asp816-->Tyr substitution, corresponds to the D81 4Y and D817Y mutations identified and characterized in the murine P815 mastocytoma and the rat RBL-2H3 mast cell leukemia cell lines. The ab sence of SCF transcripts that we found by RTPCR in the patient's blast s indicates that, also in humans, this activating mutation leads to SC F independent growth. The expression of the mutant allele on Kit signa ling may be further enhanced by trisomy of chromosome 4 (carrying the c-kit gene) in the patient's blasts. From these findings it is conclud ed that mast cells could be generated from a leukemic CD34/CD117-posit ive clone, that combines the antigenic expression of mast cell precurs or to the growth and differentiation factor-independence which was der ived by the c-kit D816Y mutation. (C) 1998 Academic Press.