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Identification of a Point Mutation in the Catalytic Domain of The Proc. Natl. Acad. Sci. USA Vol. 92, pp. 10560-10564, November 1995 Medical Sciences Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder (protein tyrosine kinase/mutation) HIROSHI NAGATA*, ALEXANDRA S. WOROBEC*, CHAD K. OH*, BADRUL A. CHOWDHURY*, SUSAN TANNENBAUMt, YOSHIFUMI SUZUKIt, AND DEAN D. METCALFE*§ *Allergic Diseases Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, tHematology Section, Clinical Pathology, Clinical Center, and tDiabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 Communicated by Richard M. Krause, National Institutes of Health, Bethesda, MD, July 6, 1995 ABSTRACT Both stem cells and mast cells express c-kit in terms of hematopathologic findings, prognosis, and possibly and proliferate after exposure to c-kit ligand. Mutations in etiology. c-kit may enhance or interfere with the ability of c-kit receptor The protooncogene c-kit encodes a transmembrane tyrosine to initiate the intracellular pathways resulting in cell prolif- kinase receptor (2, 3). Transcripts and protein products of c-kit eration. These observations suggested to us that mastocytosis are expressed on hematopoietic stem cells (4-8), mast cells (4, might in some patients result from mutations in c-kit. cDNA 9), melanocytes (10-12), and germ-cell lineages (10, 13). c-kit synthesized from peripheral blood mononuclear cells of pa- mediates signals for proliferation and maturation of these cells tients with indolent mastocytosis, mastocytosis with an asso- (14). c-kit ligand, or stem cell factor (SCF), promotes the in ciated hematologic disorder, aggressive mastocytosis, solitary vitro growth of mast cells from human CD34+ cells isolated mastocytoma, and chronic myelomonocytic leukemia unasso- from human marrow or peripheral blood mononuclear cells ciated with mastocytosis was thus screened for a mutation of (PBMCs) (15-18). These observations suggest involvement of c-kit. This analysis revealed that four of four mastocytosis c-kit in mastocytosis. In agreement with its hypothesis, it has patients with an associated hematologic disorder with pre- been reported that there is increased soluble SCF in the skin dominantly myelodysplastic features had an A -* T substitu- of patients with indolent mastocytosis (19), although this tion at nt 2468 of c-kit mRNA that causes an Asp-816 -- Val observation alone would not explain the diversity in the clinical substitution. One of one patient examined who had mastocy- patterns of disease. It has also been demonstrated that both tosis with an associated hematologic disorder had the corre- rodent mast cell lines (20) and a human c-kit+, FcsRP- cell line sponding mutation in genomic DNA. Identical or similar (HMC-1), established from peripheral blood of a patient with amino acid substitutions in mast cell lines result in ligand- mast-cell leukemia (21), exhibit point mutations in the cyto- independent autophosphorylation of the c-kit receptor. This plasmic domain of c-kit, which promote ligand-independent mutation was not identified in the patients within the other autophosphorylation of the mutant receptor (22). It is not clear disease categories or in 67 of 67 controls. The identification of whether such mutations arise in vivo or during adaptation of the point mutation Asp816Val in c-kit in patients with mas- such cells to culture. Nonetheless, there is no report of c-kit with an associated disorder abnormalities in cells directly obtained from the mastocytosis tocytosis hematologic provides population. In the present study, we thus screened for muta- insight not only into the pathogenesis of this form of masto- tions of c-kit transcripts expressed in PBMCs of patients with cytosis but also into how hematopoiesis may become dysregu- indolent mastocytosis, mastocytosis with an associated hema- lated and may serve to provide a means of confirming the tologic disorder, aggressive mastocytosis, and one patient with diagnosis, assessing prognosis, and developing intervention solitary mastocytoma. strategies. Mastocytosis is a disease characterized by mast cell hyperplasia MATERIALS AND METHODS in the bone marrow, liver, spleen, lymph nodes, gastrointestinal Patients. Blood was obtained with informed consent from tract, and skin (1). It is classified into four categories: indolent eight patients with mastocytosis, one with a solitary mastocy- mastocytosis, mastocytosis with an associated hematologic toma, and one with chronic myelomonocytic leukemia disorder, mast cell leukemia, and aggressive mastocytosis. The (CMML). The diagnosis for each patient was based on clinical most common form of the disease is indolent mastocytosis, symptomatology, physical findings, bone marrow biopsy and which involves the skin, bone marrow, and gastrointestinal aspirate, and other appropriate biopsy specimens. Blood or tract, and is characterized by symptoms caused by mast cell buffy coats were also obtained through the National Institutes mediators. Patients with mastocytosis with an associated he- of Health Clinical Center Blood Bank from 67 anonymous matologic disorder exhibit the classic mast cell lesions in their donors between the ages of 25 and 60 years. bone marrow but also have evidence of myelodysplastic syn- RNA Extraction and PCR. PBMCs were isolated by Ficoll/ dromes, myeloproliferative disorders, acute nonlymphocytic Hypaque density gradient centrifugation (density, 1.077 g/ml; leukemia, or chronic neutropenia. Aggressive mastocytosis is characterized by a rapid increase in mast cells in the liver, Abbreviations: PBMC, peripheral blood mononuclear cell; SCF, stem spleen, lymph nodes, and bone marrow. Mastocytosis may thus cell factor; CMML, chronic myelomonocytic leukemia; SSCP, single- be considered to consist of a heterogenous group of diseases strand conformation polymorphism. §To whom reprint requests should be addressed at: National Institute of Allergy and Infectious Diseases, Laboratory of Clinical Investi- The publication costs of this article were defrayed in part by page charge gation, Allergic Diseases Section, Building 10, Room 11C-205, Na- payment. This article must therefore be hereby marked "advertisement" in tional Institutes of Health, 10 Center Drive, MSC 1888, Bethesda, accordance with 18 U.S.C. §1734 solely to indicate this fact. MD 20892-1888. 10560 Downloaded by guest on September 27, 2021 Medical Sciences: Nagata et al. Proc. Natl. Acad. Sci. USA 92 (1995) 10561 Sigma), resuspended in phosphate-buffered saline, and at nt 2468. Digested fragments were then separated on a 20% counted. Approximately 1 x 10i7 PBMCs were next distributed polyacrylamide gel. cDNAs synthesized from the PBMCs of 67 into separate tubes, and total RNA was extracted by the acid unselected donors were also screened for the mutation. guanidinium/phenol/chloroform method (23). Total RNA (5 Genomic DNA Analysis. Genomic DNA from patients was ,ug) was then reverse-transcribed to cDNA with Moloney analyzed for the A -* T mutation identified in mRNA. DNA murine leukemia virus reverse transcriptase without RNase H was extracted from PBMCs and PCR-amplified by using primers activity (Life Technologies, Gaithersburg, MD) and oligo(dT) 5'-TGTGAACATCATTCAAGGCGTAC-3' and 5 '-TGT- primer. PCR was performed in 200 nM primers/all four CAAGCAGAGAATGGGTACTC-3' in PCR buffer containing dNTPs (each at 150 ,M)/20 mM Tris HCl, pH 8.4/50 mM 3 mM MgCl2. The primers are complementary to the sequence KCl/1.5 mM MgCl2/1.5 units of Taq DNA polymerase in a of introns 16 and 17 of the c-kit gene (25). The A -> T mutation 50-Al reaction solution. is located within exon 17 of the gene. A single 322-bp DNA Screening of Polymorphisms. To screen for polymorphisms fragment of the expected size was amplified. The PCR product through the entire coding region of c-kit cDNA, single-strand was digested with Hinfl and separated on an 8% polyacrylamide conformation polymorphism (SSCP) analysis of PCR products gel. Since the mutation creates a new Hinfl site, predicted was performed with 22 overlapping primer pairs (24). All fragments were 271 and 51 bp for the wild type and 257, 51, and nucleotide and amino acid numbers are according to the c-kit 14 bp for the mutation. cDNA sequence (2). Total RNA from PBMCs was reverse- Analysis of HMC-1 Cells. HMC-1 cells were also analyzed transcribed and amplified in the presence of 30 nM for A -> T mutation and were obtained directly from J. H. [,y-32P]dCTP. One microliter of the PCR product was mixed Butterfield (Mayo Clinic) (HMC-1A) and from P. Valent with 1 ,ul of 95% formamide/20 mM EDTA/0.05% bromo- (University of Vienna), who had earlier received the cells from phenol blue/0.05% xylene cyanol. Samples were denatured at J. H. Butterfield (HMC-1B). Genomic DNA and cDNA were 90°C for 3 min and loaded onto 0.4-mm-thick 6% nondena- prepared from each HMC-1 cell population and analyzed for turing polyacrylamide gels containing 90 mM Tris borate, pH the mutation by PCR amplification using the same primers 8.3/2 mM EDTA/10% (vol/vol) glycerol. Electrophoresis was followed by Hinfl digestion. carried out for 4 h at 4°C and 48 W constant power. The gel was dried on Whatman 3MM paper and autoradiographed at -70°C overnight. RESULTS Sequencing of DNA. Once a polymorphism was identified by Clinical Characteristics of Patients with Mastocytosis. SSCP
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