Trisomy 4 leading to duplication of a mutated KIT allele in acute myeloid leukemia with mast cell involvement

A G-->T transversion at nucleotide 2467 of the c-KIT gene leading to Asp816 -->Tyr (D816Y) substitution in the phosphotransferase domain has been previ ously identified in a patient with rapidly progressing AML-M2 and mast cell involvement; the patient's blasts had a 47,XY, +4,t(8;21)(q22;q22) karyoty pe. Herein Me confirm the simultaneous presence of both major chromosomal c hanges by multicolor fluorescence in situ hybridization (FISH) on interphas e CD34+ mononuclear cells. By setting up culture leukemic blasts, spontaneo us differentiation of adherent cells with mast-cell like features was prove d by histochemical and immunoenzymatic analyses. Fluorescence in situ hybri dization evidence of trisomy 4 confirmed the origin of differentiated cells from the leukemic blasts. Semiquantitative polymerase chain reaction (PCR) and phosphoimage densitometry of wild-type and mutated KIT alleles on bone morrow blasts made it possible to demonstrate that chromosome 4 trisomy le d to a double dosage of the mutated KIT allele. This finding, and that of t risomy 7 and MET mutation in hereditary renal carcinoma represent the only cases of human tumors in which an increased number of chromosomes carrying an oncogene activated by point mutation have been detected. (C) 2000 Elsevi er Science Inc. All rights reserved.