A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib

• Published in: Blood Vol. 103; no. 8; pp. 3222 - 3225
• Main Authors: Akin, Cem, Fumo, Gerard, Yavuz, Akif S., Lipsky, Peter E., Neckers, Len, Metcalfe, Dean D.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15-04-2004; The Americain Society of Hematology
• Subjects: Adult; Amino Acid Substitution; Antineoplastic Agents - therapeutic use; Benzamides; Biological and medical sciences; Bone Marrow - pathology; Female; Germ-Line Mutation; Hematologic and hematopoietic diseases; Humans; Imatinib Mesylate; In Vitro Techniques; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Mast Cells - drug effects; Mast Cells - pathology; Mastocytosis, Systemic - drug therapy; Mastocytosis, Systemic - genetics; Mastocytosis, Systemic - pathology; Medical sciences; Piperazines - therapeutic use; Proto-Oncogene Proteins c-kit - genetics; Pyrimidines - therapeutic use; Antineoplastic agent; Transmembrane protein; Mastocytosis; Imatinib; Enzyme; Transferases; C-Onc gene; Enzyme inhibitor; Malignant hemopathy; Mutation; Protein-tyrosine kinase; kit Gene
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2003-11-3816

Mutational analysis of the c-kit gene in a patient with a previously undescribed variant of mast cell disease revealed a germline mutation, Phe522Cys, within the transmembrane portion of the Kit receptor protein. Transfection experiments revealed that the mutation caused ligand-independent autophosphorylation of Kit, which was inhibited by the tyrosine kinase inhibitor imatinib mesylate. The patient's bone marrow biopsy and aspirate displayed unique pathologic features with the presence of excessive numbers of mature-appearing mast cells and absence of aberrant mast cell surface expression of CD2, CD25, and CD35. Therapy with imatinib mesylate resulted in a dramatic improvement in mast cell burden and clinical symptoms. These results highlight the significance of the transmembrane region of Kit in activation of the molecule and its importance in mast cell development and suggest a role for screening for transmembrane c-kit mutations in patients with mastocytosis in association with the decision to use imatinib mesylate. (Blood. 2004;103:3222-3225)