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

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.

scholarly journals FLT4 Mutations Are Associated with Segmental Lymphatic Dysfunction and Initial Lymphatic Aplasia in Patients with Milroy Disease

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1611
Author(s):  
Ningfei Liu ◽  
Minzhe Gao
Keyword(s):  
Tyrosine Kinase ◽  
Protein Tyrosine Kinase ◽  
Clinical Signs ◽  
Lymphatic Vessels ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Missense Mutations ◽  
History Of ◽  
Endothelial Growth Factor

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.

Quizartinib in the treatment of FLT3-internal-tandem duplication-positive acute myeloid leukemia

2019 ◽  
Vol 15 (34) ◽  
pp. 3885-3894 ◽  
Author(s):  
Shilpa Paul ◽  
Adam J DiPippo ◽  
Farhad Ravandi ◽  
Tapan M Kadia
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Tandem Duplication ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Tyrosine Kinase Domain ◽  
Missense Mutations ◽  
Internal Tandem Duplication ◽  
Acute Myeloid

FLT3 mutations, characterized by an internal-tandem duplication or missense mutations in the tyrosine kinase domain, are observed in a third of patients with newly diagnosed acute myeloid leukemia. FLT3-ITD mutations are associated with high relapse rates and short overall survival with conventional chemotherapy. Several tyrosine kinase inhibitors targeting FLT3 have been developed in an effort to improve survival and therapeutic options. This review focuses on quizartinib, a second-generation FLT3 inhibitor that has demonstrated efficacy and safety as a single agent and in combination with chemotherapy. We discuss its clinical development as well as its place in the treatment of FLT3-mutated acute myeloid leukemia among the other FLT3 inhibtors currently available and its mechanisms of resistance.

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

2004 ◽  
Vol 172 (4 Part 1) ◽  
pp. 1256-1261 ◽  
Author(s):  
LAURA S. SCHMIDT ◽  
MICHAEL L. NICKERSON ◽  
DEBORA ANGELONI ◽  
GLADYS M. GLENN ◽  
McCLELLAN M. WALTHER ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Early Onset ◽  
Renal Carcinoma ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Missense Mutations ◽  
Hereditary Papillary Renal Carcinoma

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

2018 ◽  
Vol 19 (10) ◽  
pp. 3198 ◽  
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.

Non-internal tandem duplication (ITD), non-tyrosine kinase domain (TKD) FLT3 mutations in myeloid malignancies: A brief report of 10 patients

2018 ◽  
Vol 72 ◽  
pp. 1-4
Author(s):  
Alexandra Higgins ◽  
Abhishek A. Mangaonkar ◽  
Mehrdad Hefazi ◽  
David Viswanatha ◽  
Pedro Horna ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tandem Duplication ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Internal Tandem Duplication ◽  
Myeloid Malignancies ◽  
Flt3 Mutations

scholarly journals Allogeneic transplant for FLT3-ITD mutated AML: a focus on FLT3 inhibitors before, during, and after transplant

2019 ◽  
Vol 10 ◽  
pp. 204062071988266 ◽  
Author(s):  
Abdul Hamid Bazarbachi ◽  
Rama Al Hamed ◽  
Florent Malard ◽  
Mohamad Mohty ◽  
Ali Bazarbachi
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Treatment Strategies ◽  
High Dose Chemotherapy ◽  
Kinase Domain ◽  
Genetic Alterations ◽  
Tyrosine Kinase Domain ◽  
High Dose ◽  
Npm1 Mutation ◽  
Post Transplant

FMS-like tyrosine kinase 3 ( FLT3) mutations are one of the most frequently encountered genetic alterations in acute myeloid leukemia (AML), and are generally associated with unfavorable outcomes. Several tools are currently available to provide an accurate prognosis for patients with these mutations, including FLT3 mutation type (internal tandem duplication versus tyrosine kinase domain), mutation allelic ratio (high versus low), and concurrent nucleophosmin-1 ( NPM1) mutation, to help decide on optimal treatment. Recent advances in targeted therapies have paved the way for modern treatment strategies, such as the development of FLT3 kinase inhibitors. These novel drugs can be incorporated into any treatment component, including induction and consolidation, the relapse/refractory setting, bridging for transplant, salvage post-transplant, and as prophylactic long-term post-transplant maintenance. Many challenges remain though, such as their intolerability with high-dose chemotherapy in frail patients; whether their optimal use involves watchful waiting for molecular or hematologic relapse compared with prophylactic use as maintenance; and the exact role and indication for allogeneic stem cell transplantation, which arguably remains the only curative option for these high-risk patients.

Prognostic Implication of Insertion of FLT3 Internal Tandem Duplication in the BETA-1-Sheet of the Tyrosine Kinase Domain-1

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2514-2514
Author(s):  
Sabine Kayser ◽  
Richard F. Schlenk ◽  
Frank Breitenbücher ◽  
Martina Porebski ◽  
Kerstin Wittke ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tandem Duplication ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Wild Type ◽  
Internal Tandem Duplication ◽  
Functional Regions ◽  
Integration Sites ◽  
Insertion Sites ◽  
Flt3 Internal Tandem Duplication

Abstract Background: Activating FLT3 internal tandem duplication mutations (FLT3-ITDs) occur in approximately 30% of acute myeloid leukemia (AML) patients. Expression of the FLT3-ITD receptor results in autophosphorylation of FLT3 and subsequent activation of downstream signaling. Clinically, FLT3-ITDs are associated with a dismal clinical outcome; previous explorative analyses suggest that not only FLT3-ITD per se but also the mutant/wild-type allelic ratio and/or the length of the FLT3-ITD provide prognostic information. Aims: To determine ITD insertion sites and length in FLT3-ITD mutated AML and to correlate these findings with clinical outcome. Methods: In 241 patients, DNA-based amplification of the FLT3-ITD mutation was followed by DHPLC-based separation of FLT3 mutant and wild-type fragments. Single mutated fragments were collected by a fragment collector, reamplified and sequenced. Patients [16 to 60 years of age] were entered on 3 consecutive AMLSG treatment trials [AML HD93, AML HD98A, AMLSG 07-04] all including intensive therapy. Results: Thirty-four (14.1) of the 241 patients had more than one ITD (two ITDs n=29, three ITDs n=3, four ITDs n=2). In total, 282 ITDs were analyzed. The median length was 52 nucleotides (range 15–180). For further correlations we grouped ITD integration sites according to the functional regions of FLT3: JM-domain (JMD) [amino acid (AA) 572–603, patients n =141, ITDs n=148], hinge region of JMD [AA 604–609, patients n=45, ITDs n=48], beta-1-sheet of the tyrosine kinase domain-1 (TKD1) [AA 610–615, patients n=69, ITDs n=73], and the remaining region of TKD1 [AA >615, patients n=13, ITDs n=13]. Interestingly, ITD length was strongly correlated to functional regions with shortest ITDs being present in the JMD and longest in the TKD1 (p<0.001). Clinical data were available in 239 patients showing no differences in patient characteristics (age, WBC etc.); frequencies of cooperating class II mutations (NPM1-mut n=137, CEBPA-mut n=12, MLL-PTD n=21) were equally distributed among the functionally categorized groups. The logistic regression model on induction success (IS) revealed ITD integration sites in the beta-1-sheet (odds ratio (OR) 0.25, p=0.01) and in the remaining region of TKD1 (OR 0.14, p=0.007) as well as logarithm of WBC count (OR 0.36, p=0.002) and NPM1 mutations (OR 2.04, p=0.04) as significant variables. ITD insertion in the beta-1-sheet was also significant in the Cox regression analysis on overall survival (OS) (Hazard Ratio (HR) 2.7, p=0.01). In univariable analyses, event free survival (EFS) and OS were significantly inferior in patients with ITD in the beta-1-sheet (p=0.005 and p=0.001). Of note, the proportions of patients receiving an allogeneic transplantation were comparable in both groups (61% and 67%, respectively). In multivariable analyses, neither length of ITD nor mutant/wild-type allelic ratio had an impact on OS. Conclusions: FLT3-ITD insertion sites seems to be an important prognostic marker for induction failure, EFS and OS. Therefore, not only FLT3-ITD mutation status but also ITD integration site should be prospectively analyzed in future clinical trials, in particular in the context of treatment with FLT3-tyrosine kinase inhibitors.

Mutations in the tyrosine kinase domain of FLT3 define a new molecular mechanism of acquired drug resistance to PTK inhibitors in FLT3-ITD–transformed hematopoietic cells

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2266-2275 ◽  
Author(s):  
Ksenia Bagrintseva ◽  
Ruth Schwab ◽  
Tobias M. Kohl ◽  
Susanne Schnittger ◽  
Sabine Eichenlaub ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
Cell Lines ◽  
Protein Tyrosine Kinase ◽  
Kinase Domain ◽  
Genetic Alterations ◽  
Tyrosine Kinase Domain ◽  
Protein Tyrosine ◽  
Clinical Resistance ◽  
Transformed Cell Lines

Abstract Activating mutations in the juxtamembrane domain (FLT3-length mutations, FLT3-LM) and in the protein tyrosine kinase domain (TKD) of FLT3 (FLT3-TKD) represent the most frequent genetic alterations in acute myeloid leukemia (AML) and define a molecular target for therapeutic interventions by protein tyrosine kinase (PTK) inhibitors. We could show that distinct activating FLT3-TKD mutations at position D835 mediate primary resistance to FLT3 PTK inhibitors in FLT3-transformed cell lines. In the presence of increasing concentrations of the FLT3 PTK inhibitor SU5614, we generated inhibitor resistant Ba/F3 FLT3-internal tandem duplication (ITD) cell lines (Ba/F3 FLT3-ITD-R1-R4) that were characterized by a 7- to 26-fold higher IC50 (concentration that inhibits 50%) to SU5614 compared with the parental ITD cells. The molecular characterization of ITD-R1-4 cells demonstrated that specific TKD mutations (D835N and Y842H) on the ITD background were acquired during selection with SU5614. Introduction of these dual ITD-TKD, but not single D835N or Y842H FLT3 mutants, in Ba/F3 cells restored the FLT3 inhibitor resistant phenotype. Our data show that preexisting or acquired mutations in the PTK domain of FLT3 can induce drug resistance to FLT3 PTK inhibitors in vitro. These findings provide a molecular basis for the evaluation of clinical resistance to FLT3 PTK inhibitors in patients with AML.

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