EARLY ONSET HEREDITARY PAPILLARY RENAL CARCINOMA: GERMLINE MISSENSE MUTATIONS IN THE TYROSINE KINASE DOMAIN OF THE MET PROTO-ONCOGENE

This study explored mutations in the Fms-related tyrosine kinase 4/vascular endothelial growth factor receptor 3 gene (FLT4) and lymphatic defects in patients with Milroy disease (MD). Twenty-nine patients with lower limb lymphedema were enrolled. Sixteen patients had a familial history of MD, while 13 patients exhibited sporadic MD. Clinical signs, FLT4 mutations, indocyanine green (ICG) lymphography findings, and skin tissue immunohistochemical staining results were evaluated. Twenty-eight variants in FLT4 were identified. Twelve of these have previously been reported, while 16 are novel. Of the 28 variants, 26 are missense mutations, and the remaining two comprise a splicing mutation and a non-frame shift mutation. Twenty-five variants are located in the intracellular protein tyrosine kinase domain; three are located in the extracellular immunoglobulin domain. Substantially delayed contrast-enhanced tortuous lymphatic vessels were visualized to the ankle or knee level in 15 of 23 patients who underwent ICG lymphography. No initial lymphatic vessels were visualized in skin specimens from four patients who did not exhibit lymphatic vessels during imaging analyses. No specific variant was identified in relation to the unique clinical phenotype. Segmental dysfunction of lymphatic vessels and initial lymphatic aplasia are present in MD patients with FLT4 mutations.

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Targeting Oncogenic Signaling in Mutant FLT3 Acute Myeloid Leukemia: The Path to Least Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms19103198 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3198 ◽

Cited By ~ 17

Author(s):

Dilana Staudt ◽

Heather Murray ◽

Tabitha McLachlan ◽

Frank Alvaro ◽

Anoop Enjeti ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Tyrosine Kinase ◽

Signaling Pathways ◽

Myeloid Leukemia ◽

Kinase Domain ◽

Driver Mutations ◽

Tyrosine Kinase Domain ◽

Missense Mutations ◽

Therapeutic Approaches ◽

Acute Myeloid

The identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly-targeted treatment strategies designed to improve outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3 is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD) present in 30–35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus, encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as a monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance occurs by the emergence of secondary lesions in the FLT3 gene, particularly in the second tyrosine kinase domain (TKD) at residue Asp835 (D835) to form a ‘dual mutation’ (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades; however, little is known about which divergent signaling pathways are controlled by each of the FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways deregulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise of more durable and personalized therapeutic approaches to improve treatments of FLT3 mutant AML.

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PATH-22. COMPREHENSIVE ANALYSIS OF DIVERSE LOW-GRADE NEUROEPITHELIAL TUMORS WITH FGFR1 ALTERATIONS REVEALS A DISTINCT MOLECULAR SIGNATURE OF ROSETTE-FORMING GLIONEURONAL TUMOR

Neuro-Oncology ◽

10.1093/neuonc/noaa215.703 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii168-ii169

Author(s):

Calixto-Hope G Lucas ◽

Rohit Gupta ◽

Pamela Doo ◽

Matthew Wood ◽

Marjorie Grafe ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tandem Duplication ◽

Kinase Domain ◽

Genetic Alterations ◽

Glioneuronal Tumor ◽

Tyrosine Kinase Domain ◽

Low Grade ◽

Missense Mutations ◽

Ptpn11 Mutation ◽

Pilocytic Astrocytomas

Abstract The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma (PA), dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined, nor are the histopathologic features of pilocytic astrocytomas with FGFR1 alterations versus those harboring the more common BRAF mutations or fusions. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and PA are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis refines the classification and histopathologic spectrum of LGNET with FGFR1 alterations.

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Two maternally derived missense mutations in the tyrosine kinase domain of the RET protooncogene in a patient with de novo MEN 2B

Human Molecular Genetics ◽

10.1093/hmg/4.10.1987 ◽

1995 ◽

Vol 4 (10) ◽

pp. 1987-1988 ◽

Cited By ~ 27

Author(s):

Yutaka Kitamura ◽

Nancy Scavarda ◽

Samuel A. Wells ◽

Charles E. Jackson ◽

Paul J. Goodfellow

Keyword(s):

Tyrosine Kinase ◽

De Novo ◽

Kinase Domain ◽

Tyrosine Kinase Domain ◽

Missense Mutations ◽

Ret Protooncogene ◽

Men 2B

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Targeting Oncogenic Signaling in Mutant FLT3 Acute Myeloid Leukemia: the Path to Least Resistance

10.20944/preprints201809.0435.v1 ◽

2018 ◽

Cited By ~ 1

Author(s):

Dilana Staudt ◽

Heather Murray ◽

Frank Alvaro ◽

Anoop Enjeti ◽

Nicole Verrills ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Tyrosine Kinase ◽

Signaling Pathways ◽

Myeloid Leukemia ◽

Kinase Domain ◽

Driver Mutations ◽

Tyrosine Kinase Domain ◽

Missense Mutations ◽

Therapeutic Approaches ◽

Acute Myeloid

Identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly targeted strategies designed to improve the outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3, is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD), present in 30%-35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus has encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance is induced by the emergence of secondary lesions in the FLT3 gene, particularly in the second tyrosine kinase domain at residue Asp835 (D835) to form a ‘dual mutation’ (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades however, currently little is known which divergent signaling pathways are controlled by each of these FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways regulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise for development of more durable and personalized therapeutic approaches targeting mutant FLT3, to improve the treatment of AML.

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Obvious mRNA and protein expression but absence of mutations of the RET proto-oncogene in parathyroid tumors

Acta Endocrinologica ◽

10.1530/eje.0.1340314 ◽

1996 ◽

Vol 134 (3) ◽

pp. 314-319 ◽

Cited By ~ 17

Author(s):

Takehiko Kimura ◽

Katsuhiko Yoshimoto ◽

Chisato Tanaka ◽

Toshihiro Ohkura ◽

Hiroyuki Iwahana ◽

...

Keyword(s):

Protein Expression ◽

Tyrosine Kinase ◽

Single Strand Conformation Polymorphism ◽

Kinase Domain ◽

Tyrosine Kinase Domain ◽

Missense Mutations ◽

Parathyroid Tumors ◽

Mrna And Protein Expression ◽

Pcr Method ◽

The University

Kimura T, Yoshimoto K, Tanaka C, Ohkura T, Iwahana H, Miyauchi A, Sano T. Itakura M. Obvious mRNA and protein expression but absence of mutations of the RET proto-oncogene in parathyroid tumors. Eur J Endocrinol 1996;134:314–9. ISSN 0804–4643 The study on the expression of the RET proto-oncogene in parathyroid tumors disclosed obvious mRNA expression by the reverse transcription (RT)-polymerase chain reaction (PCR) method and protein expression by Western blotting. To find out whether mutations in the cysteine-rich regions or tyrosine kinase domain of the RET proto-oncogene are etiological for parathyroid tumorigenesis, sporadic parathyroid adenomas and carcinomas, parathyroid tumors from multiple endocrine neoplasia 1. familial isolated hyperparathyroidism or hereditary hyperparathyroidism-jaw tumor syndrome were screened by PCR-single strand conformation polymorphism and PCR restriction fragment length polymorphism. Missense mutations in the cysteine-rich region, or codons 768 or 918 in the tyrosine kinase domain of the RET proto-oncogene, were not detected in any of the examined cases of parathyroid tumors. These results suggest that mutations of the RET proto-oncogene do not represent a frequent mechanism of tumorigenesis for parathyroid tumors. Mitsuo Itakura, Otsuka Department of Clinical and Molecular Nutrition, School of Medicine, The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima-city, 770 Japan

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NIDDM associated with mutation in tyrosine kinase domain of insulin receptor gene

Diabetes ◽

10.2337/diabetes.41.4.521 ◽

1992 ◽

Vol 41 (4) ◽

pp. 521-526 ◽

Cited By ~ 10

Author(s):

S. Cocozza ◽

A. Porcellini ◽

G. Riccardi ◽

A. Monticelli ◽

G. Condorelli ◽

...

Keyword(s):

Tyrosine Kinase ◽

Insulin Receptor ◽

Receptor Gene ◽

Kinase Domain ◽

Tyrosine Kinase Domain ◽

Insulin Receptor Gene

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Characteristics of BCR/ABL1 kinase domain mutations in the patients with chronic myeloid leukemia who are primary resistant to the imatinib therapy

Biolohichni systemy ◽

10.31861/biosystems2019.01.027 ◽

2019 ◽

Vol 11 (1) ◽

pp. 27-33

Author(s):

I Dmytrenko ◽

J Minchenko ◽

I Dyagil

Keyword(s):

Overall Survival ◽

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Myeloid Leukemia ◽

High Efficiency ◽

Kinase Domain ◽

Imatinib Therapy ◽

Missense Mutations ◽

Primary Resistance ◽

Kinase Domain Mutations

The chronic myeloid leukemia (CML) development is associated with the formation of the BCR/ABL1 fusion gene and the BCR/ABL1 protein with increased tyrosine kinase activity. Despite the high efficiency of targeted therapy, up to 30% of patients do not respond on such therapy i.e. are primary resistant. The presence of BCR/ABL1 kinase domain mutations is considered to be one of the reasons of tyrosin kinase inhibitors resistance. To evaluate the frequency of BCR/ABL1 kinase domain mutations in Ukrainian cohort of CML patients with primary resistance to imatinib therapy, we retrospectively studied BCR/ABL1 kinase domain mutations in peripheral blood of 107 CML patients. The nucleotide sequence was determined by direct sequencing by Sanger. Mutations were reported in 45 of 107 (41.7%) CML patients. Two mutations at a time were revealed in 8 patients. So a total of 53 mutations were found out. Among them 49 were missense-mutations and 4 - deletions of different regions of the BCR/ABL1 kinase domain gene. The missense-mutations F359I/V (12 patients), T315I (8 patients) and G250E (6 patients) were most common. By localization, the mutations majority (23 of 53) was in the P-loop, 10 mutations - in the contact site, 13 mutations - in the catalytic domain and 6 – in the A-loop. Of the detected mutations, 26 (49%) resulted in a disruption of the hydrogen bond between BCR/ABL1-tyrosine kinase and imatinib. Significant reduction in overall survival was found in patients with BCR/ABL1 kinase domain mutations compared with patients with wild-type of BCR/ABL1 gene (p=0.018). The estimated 3-year overall survival was 83.4% (95% CI: 77.0%-89.8%) and 94.3% (95% CI: 91.0%-97.3%), respectively. Therefore, mutations of the BCR/ABL1 kinase domain are one of the mechanisms of primary resistance in CML patients on imatinib therapy. The occurrence of BCR/ABL1 gene mutations impairs the prognosis of imatinib therapy response.

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Characterization of Atypical Protein Tyrosine Kinase (PTK) Genes and Their Role in Abiotic Stress Response in Rice

Plants ◽

10.3390/plants9050664 ◽

2020 ◽

Vol 9 (5) ◽

pp. 664

Author(s):

Allimuthu Elangovan ◽

Monika Dalal ◽

Gopinathan Kumar Krishna ◽

Sellathdurai Devika ◽

Ranjeet Ranjan Kumar ◽

...

Keyword(s):

Abiotic Stress ◽

Stress Response ◽

Tyrosine Kinase ◽

Tyrosine Phosphorylation ◽

Rice Genome ◽

Kinase Domain ◽

Tyrosine Kinase Domain ◽

Protein Tyrosine ◽

Dual Specificity ◽

Submergence Stress

Tyrosine phosphorylation constitutes up to 5% of the total phophoproteome. However, only limited studies are available on protein tyrosine kinases (PTKs) that catalyze protein tyrosine phosphorylation in plants. In this study, domain analysis of the 27 annotated PTK genes in rice genome led to the identification of 18 PTKs with tyrosine kinase domain. The kinase domain of rice PTKs shared high homology with that of dual specificity kinase BRASSINOSTEROID-INSENSITIVE 1 (BRI1) of Arabidopsis. In phylogenetic analysis, rice PTKs clustered with receptor-like cytoplasmic kinases-VII (RLCKs-VII) of Arabidopsis. mRNAseq analysis using Genevestigator revealed that rice PTKs except PTK9 and PTK16 express at moderate to high level in most tissues. PTK16 expression was highly abundant in panicle at flowering stage. mRNAseq data analysis led to the identification of drought, heat, salt, and submergence stress regulated PTK genes in rice. PTK14 was upregulated under all stresses. qRT-PCR analysis also showed that all PTKs except PTK10 were significantly upregulated in root under osmotic stress. Tissue specificity and abiotic stress mediated differential regulation of PTKs suggest their potential role in development and stress response of rice. The candidate dual specificity PTKs identified in this study paves way for molecular analysis of tyrosine phosphorylation in rice.

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