Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412
Joseph D. GrowneyJennifer ClarkJennifer AdelspergerRichard M. StoneDoriano FabbroJames D. GriffinD. Gary Gilliland
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Systemic mastocytosis is a rare and heterogeneous disease characterized by mast cell proliferation and activation. KIT is a transmembrane tyrosine kinase which plays a key role in mast cell growth, differentiation and survival. After interaction with its ligand, the stem cell factor, KIT dimerizes activating downstream pathways involving multiple tyrosine kinases (PI3K, JAK/STAT, RAS/ERK). Activating mutations in KIT are detected in most cases of systemic mastocytosis, being the most common KIT D816V. Therefore, since the emergence of tyrosine kinase inhibitors, KIT inhibition has been an attractive approach when facing mastocytosis treatment. Initial reports showed that only the rare KIT D816V negative cases were responsive to ITKs. However, the development of new TKIs such as midostaurin or avapritinib with activity against mast cells carrying the D816V KIT mutation, has changed the landscape of this disease.
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Interactions between products of the mouse W locus, which encodes the c-kit tyrosine kinase receptor, and the Sl locus, which encodes a ligand for c-kit receptor, which we have designated stem cell factor (SCF), have a critical role in the development of mast cells. Mice homozygous for mutations at either locus exhibit several phenotypic abnormalities including a virtual absence of mast cells. Moreover, the c-kit ligand SCF can induce the proliferation and maturation of normal mast cells in vitro or in vivo, and also can result in repair of the mast cell deficiency of Sl/Sld mice in vivo. We now report that administration of SCF intradermally in vivo results in dermal mast cell activation and a mast cell-dependent acute inflammatory response. This effect is c-kit receptor dependent, in that it is not observed when SCF is administered to mice containing dermal mast cells expressing functionally inactive c-kit receptors, is observed with both glycosylated and nonglycosylated forms of SCF, and occurs at doses of SCF at least 10-fold lower on a molar basis than the minimally effective dose of the classical dermal mast cell-activating agent substance P. These findings represent the first demonstration in vivo that a c-kit ligand can result in the functional activation of any cellular lineage expressing the c-kit receptor, and suggest that interactions between the c-kit receptor and its ligand may influence mast cell biology through complex effects on proliferation, maturation, and function.
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Abstract Contribution of SCF auto-production to neoplastic growth of mast cells. Mastocytosis is a disease accompanied by the abnormal expansion and accumulation of mast cells. Although the D816V mutation is detected in most cases of systemic mastocytosis, the mutation is rarely observed in other forms of mastocytosis, such as cutaneous mastocytosis and mast cell leukemia/sarcoma, for which the mechanism of tumorigenesis remains unknown. In this study, we demonstrated a novel mechanism of mast cell tumorigenesis via SCF autocrine/paracrine release. SCF was highly expressed in a WT KIT-expressing HRMC line, contributing to the phosphorylation of KIT. Neutralization of external SCF using a neutralizing antibody or suppression of SCF production by RNA interference inhibited the growth of HRMC cells, indicating the essential role of SCF in cell proliferation. To the best of our knowledge, this is the first report to determine the significant contribution of SCF autoproduction to neoplastic proliferation of mast cells. These results indicate the possibility that targeting SCF production may become a novel treatment for mast cell malignancies.
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c-Kit, or mast/stem cell growth factor receptor Kit, is a tyrosine kinase receptor structurally analogous to the colony-stimulating factor-1 (CSF-1) and platelet-derived growth factor (PDGF) CSF-1/PDGF receptor Tyr-subfamily. It binds the cytokine KITLG/SCF to regulate cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and it plays an essential role in melanogenesis. SCF and c-Kit are biologically active as membrane-bound and soluble forms. They can be expressed by tumor cells and cells of the microenvironment playing a crucial role in tumor development, progression, and relapses. To date, few investigations have concerned the role of SCF+/c-Kit+ mast cells in normal, premalignant, and malignant skin lesions that resemble steps of malignant melanoma progression. In this study, by immunolabeling reactions, we demonstrated that in melanoma lesions, SCF and c-Kit were expressed in mast cells and released by themselves, suggesting an autocrine/paracrine loop might be implicated in regulatory mechanisms of neoangiogenesis and tumor progression in human melanoma.
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Mastocytosis is characterized by abnormal infiltration of mast cells into various organs. An activating mutation in c‐ kit , involving an A → T substitution at nucleotide 2648 has recently been described in some patients with mastocytosis. We describe a 12‐year‐old girl with this mutation in her bone marrow cells at diagnosis with a myelodysplastic syndrome (MDS) without evidence of mastocytosis, and then in peripheral blood mononuclear cells 1 year later after the emergence of mastocytosis. The role of the c‐Kit receptor and its ligand stem cell factor (SCF) in the pathogenesis of the disease was analysed in marrow cell clonogenic assays. We show that the genetic abnormalities in the patient resulted in factor‐independent growth and hypersensitivity of primitive progenitors to SCF, with increased production of mast cells. Increased apoptosis and cluster formation, consistent with the myelodysplastic nature of the disorder, accompanied accumulation of abnormal cells with increasing concentrations of SCF.
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Microphthalmia-associated transcription factor
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Mastocytosis is characterized by the abnormal proliferation of mast cells in 1 or more organs. In most patients, a mutation is present in the gene for C-KIT, resulting in deregulation of the c-kit receptor. Imatinib mesylate is a potent inhibitor of c-kit receptor tyrosine kinase activity. Therefore, the authors evaluated the efficacy and safety of imatinib mesylate as treatment for patients with systemic mastocytosis.Patients with systemic mastocytosis received imatinib mesylate orally at a dose of 400 mg once daily for 3 to 6 months. Low doses of prednisone were added during the first 2 weeks. Endpoints were reductions in serum tryptase, urinary N-methylhistamine excretion, skin lesions, the number of mast cells in bone marrow sections, hepatomegaly and/or splenomegaly, and symptoms.Of 14 patients who were included in the study, 11 patients had the D816V mutation. One patient expressed the FIP1L1-PDGFR-alpha rearrangement gene. In 2 patients, no mutation was found. In 10 patients, serum tryptase levels decreased >20%. In all patients, urinary N-methylhistamine excretion was reduced. In 8 of 13 evaluable patients, the number of mast cells in the bone marrow decreased. Skin symptoms diminished in 5 of 9 patients. Hepatosplenomegaly improved in 3 of 6 patients. Symptoms decreased in 8 of 13 patients. In all patients who had the D816V mutation, reductions in > or =2 endpoints were achieved. In the patient who expressed the FIP1L1-PDGFR-alpha rearrangement gene, a complete response was attained. In general, imatinib mesylate was tolerated well.Imatinib mesylate was effective in patients with systemic mastocytosis, including those who had the D816V mutation.
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Stem cell factor (SCF), also known as mast cell growth factor, kit ligand, and steel factor, is the ligand for the tyrosine kinase receptor (SCFR) that is encoded by the c-kit proto-oncogene. We analyzed the effects of recombinant human SCF (r-hSCF, 5-50 micrograms/kg/day, injected subcutaneously) on mast cells and melanocytes in a phase I study of 10 patients with advanced breast carcinoma. A wheal and flare reaction developed at each r-hSCF injection site; by electron microscopy, most dermal mast cells at these sites exhibited extensive, anaphylactic-type degranulation. A 14-d course of r-hSCF significantly increased dermal mast cell density at sites distant to those injected with the cytokine and also increased both urinary levels of the major histamine metabolite, methyl-histamine, and serum levels of mast cell alpha-tryptase. Five subjects developed areas of persistent hyperpigmentation at r-hSCF injection sites; by light microscopy, these sites exhibited markedly increased epidermal melanization and increased numbers of melanocytes. The demonstration that r-hSCF can promote both the hyperplasia and the functional activation of human mast cells and melanocytes in vivo has implications for our understanding of the role of endogenous SCF in health and disease. These findings also indicate that the interaction between SCF and its receptor represents a potential therapeutic target for regulating the numbers and functional activity of both mast cells and cutaneous melanocytes.
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