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 previously 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) karyotype. Herein we confirm the simultaneous presence of both major chromosomal changes by multicolor fluorescence in situ hybridization (FISH) on interphase CD34+ mononuclear cells. By setting up culture leukemic blasts, spontaneous differentiation of adherent cells with mast-cell like features was proved by histochemical and immunoenzymatic analyses. Fluorescence in situ hybridization 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 marrow blasts made it possible to demonstrate that chromosome 4 trisomy led to a double dosage of the mutated KIT allele. This finding, and that of trisomy 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.