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1	Analysis of NTRK1 gene rearrangement and BRAF gene mutation in papillary thyroid carcinoma Li, Chun-Liang 15 July 2004 (has links) Activating mutations of genes coding for two different tyrosine kinase receptor, either RET or NTRK1 (also named TRKA), as well as of RAS or BRAF gene are associated with human thyroid papillary carcinoma (PTC). RET or NTRK1 protooncogene encodes a cell-surface transmembrane tyrosine kinase receptor with nerve growth factor as its lignand. Oncogenic potential of these two genes in thyrocytes results from replacement of their 5' portion by regulatory parts of other genes, leading to constitutive activation of their tyrosine kinase activity. The four reported oncogenic rearrangements of NTRK1 (TRK) are the consequences of fusion of its tyrosine kinase domain with one of the three genes (TPM3 gene, TPR gene, TFG gene). In our previous study, a PTC sample was found to express the NTRK1 tyrosine kinase domain without harboring NTRK1 rearrangement. We, therefore, assumed that there might have a novel NTRK1 rearrangement in this sample. 5¡¦RACE strategy was employed to clone the unknown 5¡¦end. Sequence of the cloned DNA fragment demonstrated that it is an aberrant transcription product containing an unspliced intron 9. In addition, the variant of NTRK1 wild type termed TRKA¢¹, which lacks exon 9, was also detected in this particular specimen. We conclude that amplification of TK domain of NTRK1 may serve as a rapid screening method for the presence of NTRK1-related transcript in PTCs. Mutations of the BRAF protein serine/threonine kinase gene have recently been identified in a variety of human cancers, especially in melanoma and papillary thyroid carcinomas. Among benign and malignant thyroid tumors, BRAF V599E mutations were reported to be restricted to papillary carcinomas. In this study, we analyzed mutations of BRAF in conjunction with our previous studies on RAS, RET rearrangement and NTRK1 rearrangement in PTCs to investigate genetic alterations in the RAS/RAF/MEK/MAPK kinase pathway. BRAF V599E mutations were detected in 49 of 105 (47%) PTCs but not in other type of thyroid tumor. There was no overlap between papillary carcinomas harboring RET rearrangement, NTRK1 rearrangement and BRAF mutations. Correlation between BRAF mutations and various clinicopathological parameters in 101 papillary carcinomas did not reveal any association with age, sex, tumor size, cervical lymph node metastasis, extrathyroidal extension, distant metastases and clinical stage. We conclude that BRAF mutations are restricted to papillary carcinomas in thyroid tumor. The overall frequencies in our study are in line with data previously reported. In Taiwan, BRAF mutation is the most prevalent oncogene in papillary thyroid carcinomas so far identified. 5'race BRAF NTRK1 PTC thyroid
2	Mécanismes de la leucémogenèse basophile induite par la translocation X;6 avec fusion MYB-GATA1 / MYB-GATA1 fusion promotes basophilic leukaemia : involvement of IL33 and nerve growth factor receptors Ducassou, Stéphane 29 November 2016 (has links) La leucémie aiguë à basophile du Nourrisson est un sous-type rare de leucémie aiguë myéloïde.Notre équipe avait précédemment participé à la caractérisation moléculaire de la translocationrécurrente t(X;6)(p11;q23) générant un gène de fusion MYB-GATA1 chez les nourrissons desexe masculin. Pour mieux comprendre son rôle, le facteur de transcription MYB-GATA1résultant de cette fusion a été exprimé dans des cellules progénitrices de l’hématopoïèsehumaine, CD34+ avant xénogreffe chez des souris immunodéficientes. Les cellules exprimantMYB-GATA1 présentaient une augmentation de l’expression des marqueurs d’immaturité(CD34), des marqueurs de la lignée granuleuse (CD33, CD117) et des signes de différenciationbasophile (CD203c, FcƐRI). Des cellules de lignée UT-7 ont également montré descaractéristiques de différenciation basophile après transduction par MYB-GATA1. Une analysetranscriptomique a permis de mettre en évidence 9 gènes dérégulés à la fois par la présence deMYB-GATA1 et par la différenciation basophile. L’augmentation de l’expression de 3 de cesgènes (CCL23, IL1RL1 et NTRK1) a été confirmée en RT-PCRq dans des cellules CD34+transduites avec MYB-GATA1. L’IL-33 (Interleukine 33) et le NGF (Nerve Growth Factor),les ligands respectifs de IL1RL1 et NTRK1, augmentent la différenciation basophile de cellulesUT-7 exprimant MYB-GATA1, démontrant l’importance de ces voies de signalisation dans ladifférenciation basophiles de cellules leucémiques et de cellules primaires de l’hématopoïèsehumaine CD34+. Enfin une expérience utilisant la luciférase a confirmé que MYB et MYBGATA1augmentaient l’activité des facteurs de transcription NTRK1 et IL1RL1 conduisant àl’acquisition de caractéristiques basophiles. Nos résultats soulignent ainsi l’importance desrécepteurs à l’IL-33 et au NGF dans la différenciation basophile des cellules normales etleucémiques. / Acute basophilic leukaemia (ABL) is a rare subtype of acute myeloblastic leukaemia. Wepreviously described a recurrent t(X;6)(p11;q23) translocation generating a MYB-GATA1fusion gene in male infants with ABL. To better understand its role, the chimeric MYB-GATA1transcription factor was expressed in CD34-positive hematopoietic progenitors which weretransplanted into immunodeficient mice. Cells expressing MYB-GATA1 showed increasedexpression of markers of immaturity (CD34), of granulocytic lineage (CD33, CD117) and ofbasophilic differentiation (CD203c, FcƐRI). UT-7 cells also showed basophilic differentiationafter MYB-GATA1 transfection. A transcriptomic study identified 9 genes deregulated by bothMYB-GATA1 and by basophilic differentiation. Induction of three of these genes (CCL23,IL1RL1 and NTRK1) was confirmed in MYB-GATA1-expressing CD34-positive cells byRTqPCR. IL-33 and NGF (Nerve Growth Factor), the ligands of IL1RL1 and NTRK1,respectively, enhanced the basophilic differentiation of MYB-GATA1-expressing UT-7 cells,thus demonstrating the importance of this pathway in basophilic differentiation of leukemiccells and CD34 positive primary cells. Finally, gene reporter assays confirmed that MYB andMYB-GATA1 activated NTRK1 and IL1RL1 transcription leading to basophilic skewing ofthe blasts. Our results highlight the role of IL-33 and NGF receptors in basophilic differentiationof normal and leukemic cells. Basophiles MYB-GATA1 Leucémie IL1RL1 NTRK1 Basophils MYB-GATA1 Leukaemia IL1RL1 NTRK1
3	Inhibition of EGFR and MEK surmounts entrectinib resistance in a brain metastasis model of NTRK1-rearranged tumor cells / EGFRとMEKの阻害は、NTRK1融合遺伝子を有する腫瘍細胞の脳転移においてエヌトレクチニブ耐性を克服する Suzuki, Chiaki 23 May 2023 (has links) 京都大学 / 新制・課程博士 / 博士(医学) / 甲第24781号 / 医博第4973号 / 新制\|\|医\|\|1066(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授中島貴子, 教授溝脇尚志, 教授武藤学 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM acquired resistance NTRK1-G595R repotrectinib tropomyosin-related kinase inhibitors 490
4	Micro RNA-Mediated regulation of the full-length and truncated isoforms of human neurotrophic tyrosine kinase receptor type 3 (NTRK 3) Guidi, Mònica 13 January 2009 (has links) Neurotrophins and their receptors are key molecules in the development of thenervous system. Neurotrophin-3 binds preferentially to its high-affinity receptorNTRK3, which exists in two major isoforms in humans, the full-length kinaseactiveform (150 kDa) and a truncated non-catalytic form (50 kDa). The twovariants show different 3'UTR regions, indicating that they might be differentiallyregulated at the post-transcriptional level. In this work we explore howmicroRNAs take part in the regulation of full-length and truncated NTRK3,demonstrating that the two isoforms are targeted by different sets of microRNAs.We analyze the physiological consequences of the overexpression of some of theregulating microRNAs in human neuroblastoma cells. Finally, we providepreliminary evidence for a possible involvement of miR-124 - a microRNA with noputative target site in either NTRK3 isoform - in the control of the alternativespicing of NTRK3 through the downregulation of the splicing repressor PTBP1. / Las neurotrofinas y sus receptores constituyen una familia de factores crucialespara el desarrollo del sistema nervioso. La neurotrofina 3 ejerce su funciónprincipalmente a través de una unión de gran afinidad al receptor NTRK3, del cualse conocen dos isoformas principales, una larga de 150KDa con actividad de tipotirosina kinasa y una truncada de 50KDa sin dicha actividad. Estas dos isoformasno comparten la misma región 3'UTR, lo que sugiere la existencia de unaregulación postranscripcional diferente. En el presente trabajo se ha exploradocomo los microRNAs intervienen en la regulación de NTRK3, demostrando que lasdos isoformas son reguladas por diferentes miRNAs. Se han analizado lasconsecuencias fisiológicas de la sobrexpresión de dichos microRNAs utilizandocélulas de neuroblastoma. Finalmente, se ha estudiado la posible implicación delmicroRNA miR-124 en el control del splicing alternativo de NTRK3 a través de laregulación de represor de splicing PTBP1. RISC complex retinoic acid renilla luciferase real-time quantitative PCR PTBP1 pri-miRNA pre-miRNA post-transcriptional regulation piRNA PicTar pGL4.13 PCR P-body p75NTR overexpression NTRK3 NTRK2 NTRK1 non-coding RNAs NGF neurotrophin neurotrophic signaling neuronal differentiation neurodevelopment neuroblastoma nervous system mRNA miRNA target prediction miRNA profiling miRNA mimic miRNA microarray miRNA inhibitor miRanda microRNA microarray luciferase assay Ingenuity Pathway Analysis (IPA) heLa cells gene silencing gene regulation full-length isoform (FL-NTRK3) firefly luciferase ERK disease dicer cancer development BDNF argonaute alternative splicing 3'UTR RNAhybrid RT-PCR SH-SY5Y cells siRNA standard error synaptic plasticity target validation TargetScan transfection translational repression TrkA TrkB TrkC truncated isoform (TR-NTRK3) tyrosine kinase (TK) western blot 575 61

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