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 is supported by the development of mast cells from CD34+/CD117+(c-kit) myeloid precursors. Growth factor independence, neoplastic transformation and differentiation of mast cells were found in association with c-kit activating mutations in both murine and human mastocytoma and mast cell diseases. We have identified a novel c-kit mutation (D816Y) in peripheral blood mononuclear cells from a patient with AML (M2), 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-kit gene resulting in Asp816-->Tyr substitution, corresponds to the D814Y and D817Y mutations identified and characterized in the murine P815 mastocytoma and the rat RBL-2H3 mast cell leukemia cell lines. The absence of SCF transcripts that we found by RTPCR in the patient's blasts indicates that, also in humans, this activating mutation leads to SCF independent growth. The expression of the mutant allele on Kit signaling may be further enhanced by trisomy of chromosome 4 (carrying the c-kit gene) in the patient's blasts. From these findings it is concluded that mast cells could be generated from a leukemic CD34/CD117-positive clone, that combines the antigenic expression of mast cell precursor to the growth and differentiation factor-independence which was derived by the c-kit D816Y mutation.
Department of Biology and Genetics, Medical Faculty, University of Milan, Italy.
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Beghini
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Cairoli
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E
Morra
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Larizza
D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D001853:Bone Marrow / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D017809:Fatal Outcome; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D006801:Humans; D007946:Leukemia, Mast-Cell / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D008297:Male; D008407:Mast Cells / Q000166:cytology*; D012515:Mast-Cell Sarcoma / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000166:cytology*; D017354:Point Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis / Q000235:genetics*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019089:Stem Cell Factor / Q000502:physiology; D014407:Tumor Cells, Cultured
D018952:Antigens, CD34; D004273:DNA, Neoplasm; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit