Classes of c-KIT activating mutations: proposed mechanisms of action and implications for disease classification and therapy

Longley, B. Jack; Reguera, Maria Jose; Ma, Yongsheng

doi:10.1016/s0145-2126(01)00028-5

Cited by 294 publications

(211 citation statements)

References 35 publications

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“…Recently, an increasing number of such mutations have been reported in samples derived either from patients with mastocytosis (Nagata et al, 1995;Longley et al, 1996;Pignon et al, 1997), AML (Beghini et al, 1998(Beghini et al, , 2000Sperr et al, 1998) and GIST (Hirota et al, 1998), or from tumor mast cell lines (Furitsu et al, and Ba/F3KITG559 (m) cultivated without growth factor were incubated for 48 h at the indicated concentrations of LY294002 and SB202190 in a proliferation assay as described in Figure 2a 1993; Tsujimura et al, 1994). All these mutations have been almost exclusively clustered in two regions: the JMD-cytoplasmic region and a hot spot in the kinase region around the 816 hKIT residue (Pignon et al, 1997, Longley et al, 2001 (Figure 1).…”

Section: Discussionmentioning

confidence: 99%

Signal transduction by several KIT juxtamembrane domain mutations

et al. 2003

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Mutations of KIT receptor tyrosine kinase are found in the majority of patients with mastocytosis and in most gastrointestinal stromal tumors. Oncogenic KIT mutations in GISTs are located in the KIT juxtamembrane domain (JMD), while codon 816 in the KIT kinase domain is mutated in systemic mastocytosis. We describe and characterize a mutation in the KIT-JMD named KD27. We show that KD27 mutant is constitutively dimerized and phosphorylated. KD27 ectopic expression renders both the Ba/F3 cell line and primary cultures of bone marrow mast cells independent of cytokines for proliferation and cell survival. The classical signaling pathways activated by wild-type KIT upon ligand stimulation are constitutively activated by KD27 and other JMD mutations. However, a side-to-side comparison revealed differences between the wild-type and JMD mutations. First, in vitro kinase assays reveal a change in peptide substrate specificity. Second, STAT proteins are preferentially phosphorylated by KIT mutants. Third, inhibitors of KIT kinase are more efficient on JMD mutations than on WT KIT. We conclude that KD27 is a new oncogenic KIT mutation showing constitutive activation of downstream signaling pathways, and suggest that specific pathways are activated by oncogenic KIT.

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Section: Discussionmentioning

confidence: 99%

Signal transduction by several KIT juxtamembrane domain mutations

et al. 2003

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“…Until the year 2000, the prognosis for patients with metastatic GISTs was very poor, but the advent of imatinib mesylate (formerly STI571, [Glivec]; Novartis, Basel, Switzerland) has dramatically changed this perception (5)(6)(7). By analogy to its inhibitory effect on the BCR-ABL tyrosine kinase in CML, it was postulated that imatinib mesylate would selectively inhibit the constitutive activity of c-kit proto-oncogene which encodes the receptor (KIT) tyrosine kinase in GISTs (8)(9)(10)(11). Here, we report a case of malignant GIST of the small intestine complicated with pulmonary tuberculosis during treatment with imatinib mesylate.…”

Section: Introductionmentioning

confidence: 93%

Malignant Gastrointestinal Stromal Tumor of the Small Intestine Complicated with Pulmonary Tuberculosis during Treatment with Imatinib Mesylate

et al. 2005

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We describe a patient who had a metastatic gastrointestinal stromal tumor (GIST) after previous failed extensive therapy, including multiple surgeries and hepatic artery embolization. Within a few months of starting administration of imatinib mesylate, the patient exhibited a clinical response with grade 3 neutropenia, when pulmonary tuberculosis developed. A c-kit mutation in exon 11 was detected only in metastatic liver specimens. It is unclear whether or not pulmonary tuberculosis may be induced by imatinib mesylate treatment, but caution is warranted in immunocompromised GIST patients. This is the first report of tuberculosis associated with neutropenia during imatinib mesylate treatment.

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“…13 Most of these translocations produce chimeric transcription factors, which presumably deregulate the expression of several target genes. 14 In the case of gastrointestinal stromal tumors (GIST), a distinct somatic mutation has been described in KIT, [15][16][17] which leads to ligand-independent constitutive activation of its encoded receptor tyrosine kinase. This in turn results in altered cell proliferation and tumorigenesis.…”

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confidence: 99%

Classification and Subtype Prediction of Adult Soft Tissue Sarcoma by Functional Genomics

Segal

Pavlidis

Antonescu

et al. 2003

The American Journal of Pathology

213

127

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Adult soft tissue sarcomas are a heterogeneous group of tumors, including well-described subtypes by histological and genotypic criteria, and pleomorphic tumors typically characterized by non-recurrent genetic aberrations and karyotypic heterogeneity. The latter pose a diagnostic challenge, even to experienced pathologists. We proposed that gene expression profiling in soft tissue sarcoma would identify a genomicbased classification scheme that is useful in diagnosis. RNA samples from 51 pathologically confirmed cases, representing nine different histological subtypes of adult soft tissue sarcoma, were examined using the Affymetrix U95A GeneChip. Statistical tests were performed on experimental groups identified by cluster analysis, to find discriminating genes that could subsequently be applied in a support vector machine algorithm. Synovial sarcomas, round-cell/myxoid liposarcomas, clear-cell sarcomas and gastrointestinal stromal tumors displayed remarkably distinct and homogenous gene expression profiles. Pleomorphic tumors were heterogeneous. Notably , a subset of malignant fibrous histiocytomas , a controversial histological subtype , was identified as a distinct genomic group. The support vector machine algorithm supported a genomic basis for diagnosis, with both high sensitivity and specificity. In conclusion, we showed gene expression profiling to be useful in classification and diagnosis, providing insights into pathogenesis and pointing to potential new therapeutic targets of soft tissue sarcoma. cases. 1 There are over 50 subtypes of this disease, which are currently diagnosed by genetic and morphological criteria. 2,3 Those most frequently seen include liposarcoma, leiomyosarcoma, malignant fibrous histiocytoma (MFH), fibrosarcoma, and synovial sarcoma. 4 The molecular classification of STS includes two major categories on the basis of 1) a single recurrent genetic alteration, such as chromosomal translocations (synovial sarcoma, myxoid/round-cell liposarcoma, clear-cell sarcoma) or activating mutation (KIT), or 2) non-recurrent genetic aberrations, which form part of a complex abnormal karyotype. 5 It is possible to classify some STS by their recurrent chromosomal translocations or somatic mutation, 6 such as the presence of SYT-SSX fusion transcript in synovial sarcoma, 7,8 EWS-ATF1 in clear-cell sarcoma, 9,10 TLS-CHOP in myxoid/round-cell liposarcoma 11,12 and ASPL-TFE3 in alveolar soft-part sarcoma. 13 Most of these translocations produce chimeric transcription factors, which presumably deregulate the expression of several target genes. 14 In the case of gastrointestinal stromal tumors (GIST), a distinct somatic mutation has been described in KIT, 15-17 which leads to ligand-independent constitutive activation of its encoded receptor tyrosine kinase. This in turn results in altered cell proliferation and tumorigenesis.The group of tumors characterized by numerous, nonrecurrent chromosomal alterations includes MFH, conventional fibrosarcoma, leiomyosarcoma, de-differentiated liposarcoma and pleomo...

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Classes of c-KIT activating mutations: proposed mechanisms of action and implications for disease classification and therapy

Cited by 294 publications

References 35 publications

Signal transduction by several KIT juxtamembrane domain mutations

Signal transduction by several KIT juxtamembrane domain mutations

Malignant Gastrointestinal Stromal Tumor of the Small Intestine Complicated with Pulmonary Tuberculosis during Treatment with Imatinib Mesylate

Classification and Subtype Prediction of Adult Soft Tissue Sarcoma by Functional Genomics

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