scholarly journals Deletions in FLT-3 juxtamembrane domain define a new class of pathogenic mutations: case report and systematic analysis

2021 ◽  
Vol 5 (9) ◽  
pp. 2285-2293
Author(s):  
David J. Young ◽  
Bao Nguyen ◽  
Ruiqi Zhu ◽  
Jaesung Seo ◽  
Li Li ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Novel Mutation ◽  
Common Mutation ◽  
Juxtamembrane Domain ◽  
Systematic Analysis ◽  
Downstream Signaling ◽  
Activating Mutations ◽  
New Class ◽  
Systematic Understanding

Abstract The FMS-like tyrosine kinase 3 (FLT-3) is the most frequently mutated gene in acute myeloid leukemia (AML), a high-risk feature, and now the target of tyrosine kinase inhibitors (TKIs), which are approved and in development. The most common mutation is the internal tandem duplication (ITD). We present a novel mutation, FLT-3/Q575Δ, identified in a patient with AML through next-generation sequencing (NGS). This mutation is activating, drives downstream signaling comparable to FLT-3/ITD, and can be targeted using available FLT-3 TKIs. We present the results of a systematic analysis that identified Y572Δ, E573Δ, and S574Δ as similarly activating and targetable deletions located in the FLT-3 juxtamembrane domain (JMD). These mutations target key residues in the JMD involved in the interactions within FLT-3 that regulate its activation. Our results suggest a new class of FLT-3 mutations that may have an impact on patient care and highlight the increasing importance of a systematic understanding of FLT-3 mutations other than ITD. It is likely that, as NGS becomes more commonly used in the diagnosis of patients with AML, these and other activating mutations will be discovered with increasing frequency.

Sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor

Blood ◽  
2003 ◽  
Vol 102 (2) ◽  
pp. 646-651 ◽  
Author(s):  
Rebekka Grundler ◽  
Christian Thiede ◽  
Cornelius Miething ◽  
Christine Steudel ◽  
Christian Peschel ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Point Mutations ◽  
Kinase Domain ◽  
Hek 293 ◽  
Constitutive Activation ◽  
Downstream Signaling ◽  
Activating Mutations ◽  
Experimental Systems

AbstractActivating mutations of FLT3 have been detected in patients with acute myeloid leukemia (AML). Two distinct types of FLT3 mutations are most common: internal tandem duplication (ITD) of sequences coding for the juxtamembrane domain and point mutations at codon 835 (Asp835) within the kinase domain. Both types of mutations constitutively activate the tyrosine kinase activity of FLT3 in experimental systems and result in factor-independent proliferation of Ba/F3 and 32D cells. Recently, novel mutations within the activation loop were identified in patients with AML: deletion of isoleucine 836 (Ile836del) and an exchange of isoleucine 836 to methionine plus an arginine insertion (Ile836Met+Arg). To examine whether the Ile836 mutations result in constitutive activation of the FLT3 receptor, we introduced both mutant FLT3 cDNAs transiently into HEK 293 cells. Both mutant FLT3 receptors were constitutively autophosphorylated in the absence of ligand and kinase activity led to constitutive activation of downstream signaling cascades as determined by activation of the STAT5 (signal transducer and activator of transcription 5) pathway. When stably expressed in the growth factor–dependent cell lines Ba/F3 and 32D, both deletion and insertion mutants led to factor-independent proliferation, indicating that both mutants have transforming capabilities. We then examined the sensitivity of the FLT3 ITD, FLT3 Asp835Tyr, and the novel FLT3 receptor mutants toward the kinase inhibitors AG1296, PKC412, and SU5614. We show that these FLT3 kinase inhibitors have distinct inhibitory potencies against different activating FLT3 receptor mutants. These results suggest that it may be useful to determine the exact kind of FLT3 mutation when applying receptor kinase inhibitors in clinical trials.

Point mutations in the juxtamembrane domain of FLT3 define a new class of activating mutations in AML

Blood ◽  
2006 ◽  
Vol 107 (9) ◽  
pp. 3700-3707 ◽  
Author(s):  
Carola Reindl ◽  
Ksenia Bagrintseva ◽  
Sridhar Vempati ◽  
Susanne Schnittger ◽  
Joachim W. Ellwart ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Apoptotic Cell ◽  
Point Mutations ◽  
Kinase Domain ◽  
Structural Basis ◽  
Tyrosine Kinase Domain ◽  
Juxtamembrane Domain ◽  
Downstream Target ◽  
Activating Mutations ◽  
New Class

In acute myeloid leukemia (AML), two clusters of activating mutations are known in the FMS-like tyrosine kinase-3 (FLT3) gene: FLT3-internal tandem duplications (FLT3-ITDs) in the juxtamembrane (JM) domain in 20% to 25% of patients, and FLT3 point mutations in the tyrosine-kinase domain (FLT3-TKD) in 7% to 10% of patients, respectively. Here, we have characterized a new class of activating point mutations (PMs) that cluster in a 16-amino acid stretch of the juxtamembrane domain of FLT3 (FLT3-JM-PMs). Expression of 4 FLT3-JM-PMs in interleukin-3 (IL-3)-dependent Ba/F3 cells led to factor-independent growth, hyperresponsiveness to FLT3 ligand, and resistance to apoptotic cell death. FLT3-JM-PM receptors were autophosphorylated and showed a higher constitutive dimerization rate compared with the FLT3-wild-type (WT) receptor. As a molecular mechanism, we could show activation of STAT5 and up-regulation of Bcl-x(L) by all FLT3-JM-PMs. The FLT3 inhibitor PKC412 abrogated the factor-independent growth of FLT3-JM-PM-expressing cells. Compared with FLT3-ITD and FLT3-TKD mutants, the FLT3-JM-PMs showed a weaker transforming potential related to lower autophosphorylation of the receptor and its downstream target STAT5.Mapping of the FLT3-JM-PMs on the crystal structure of FLT3 showed that these mutations reduce the stability of the autoinhibitory JM domain, and provides a structural basis for the transforming capacity of this new class of gain-of-function mutations of FLT3.

Point Mutations Found in the Juxtamembrane Domain of FLT3 Define a New Class of Activating Mutations in AML.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4388-4388
Author(s):  
Carola Reindl ◽  
Ksenia Bagrintseva ◽  
Susanne Schnittger ◽  
Joachim W. Ellwart ◽  
Katja Wenig ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Apoptotic Cell ◽  
Point Mutations ◽  
Kinase Domain ◽  
Structural Basis ◽  
Tyrosine Kinase Domain ◽  
Juxtamembrane Domain ◽  
Activating Mutations ◽  
New Class ◽  
Amino Acid Stretch

Abstract In acute myeloid leukemia (AML) FMS-like tyrosine kinase-3 (FLT3) has been shown to be mutated in about one third of patients. Until now, two distinct activating mutations are known: FLT3-length mutations (FLT3-LM) in the juxtamembrane (JM) domain in 20–25% and FLT3-point mutations in the tyrosine-kinase domain (FLT3-TKD) in 7–10% of patients. Here, we have characterized a new class of activating point mutations (PM) that cluster in a 16 amino acid stretch of the juxtamembrane domain of FLT3 (FLT3-JM-PM). Stable expression of four distinct FLT3-JM-PM in IL-3 dependent murine Ba/F3 cells led to factor-independent growth, hyperresponsiveness to FLT3-ligand and resistance to apoptotic cell death compared to FLT3-WT-expressing cells. As a molecular mechanism, we could show activation of STAT5 and upregulation of Bcl-x(L) by all FLT3-JM-PM. A selective FLT3-inhibitor, PKC412, was able to abrogate the factor-independent growth of FLT3-JM-PM. Mapping of the FLT3-JM-PM on the crystal structure of FLT3 showed that these mutations probably reduce the stability of the JM domain in the autoinhibitory conformation, and provide a structural basis for their transforming capacity. Our results show that point mutations in the autoinhibitory JM domain represent a new class of gain-of-function mutations able to activate the transforming potential of FLT3.

scholarly journals Registered report: Widespread potential for growth factor-driven resistance to anticancer kinase inhibitors

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Edward Greenfield ◽  
Erin Griner ◽  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Signaling Pathways ◽  
Receptor Tyrosine Kinase ◽  
Cancer Biology ◽  
Kinase Inhibitors ◽  
Open Science ◽  
Downstream Signaling ◽  
Rtk Inhibitors ◽  
Block Sensitivity

The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of 50 papers in the field of cancer biology published between 2010 and 2012. This Registered Report describes the proposed replication plan of key experiments from ‘Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors’ by Wilson and colleagues, published in Nature in 2012 (<xref ref-type="bibr" rid="bib20">Wilson et al., 2012</xref>). The experiments that will be replicated are those reported in Figure 2B and C. In these experiments, Wilson and colleagues show that sensitivity to receptor tyrosine kinase (RTK) inhibitors can be bypassed by various ligands through reactivation of downstream signaling pathways (Figure 2A; <xref ref-type="bibr" rid="bib20">Wilson et al., 2012</xref>), and that blocking the receptors for these bypassing ligands abrogates their ability to block sensitivity to the original RTK inhibitor (Figure 2C; <xref ref-type="bibr" rid="bib20">Wilson et al., 2012</xref>). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published by eLife.

Efficacy of EGFR tyrosine kinase inhibitors in patients having EGFR-activating mutations with or without BIM polymorphisms

2020 ◽  
Vol 86 (4) ◽  
pp. 517-525
Author(s):  
Ryo Ariyasu ◽  
Noriko Yanagitani ◽  
Kenichi Tadokoro ◽  
Toshikazu Yamaguchi ◽  
Ken Uchibori ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Activating Mutations ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors

Tyrosine kinase inhibitors: New class of antimalarials on the horizon?

2015 ◽  
Vol 55 (2) ◽  
pp. 119-126 ◽  
Author(s):  
Vrushali Pathak ◽  
Roshan Colah ◽  
Kanjaksha Ghosh
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
New Class

scholarly journals Tyrosine kinases in etiopathogenesis and therapy of malignant diseases: c-kit activating mutations

2010 ◽  
Vol 63 (5-6) ◽  
pp. 380-386
Author(s):  
Karmen Stankov ◽  
Gordana Bogdanovic ◽  
Stevan Popovic
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Tyrosine Kinases ◽  
Malignant Disease ◽  
Therapeutic Response ◽  
Kinase Inhibitors ◽  
New Technologies ◽  
Cancer Therapeutics ◽  
Activating Mutations ◽  
Gene Expression Levels

Introduction. In the last 15 years, the introduction of molecular biology methods and techniques for identifying mutations and measuring gene expression levels of mutated genes since recently, have enabled precise molecular diagnostics, classification and assessment of prognosis and therapeutic response of malignant disease to specific therapies. The increased knowledge of the cancer genome and the introduction of multiple new technologies in cancer research have significantly improved the drug discovery process, leading to key success in targeted cancer therapeutics, including tyrosine kinase inhibitors. Tyrosine kinase inhibitors are the molecular targeted neoadjuvant and adjuvant therapy of various malignancies. Many more results which are expected from ongoing trials are necessary to specify the appropriate dosages, stages at which to start the treatment, and which therapeutic combinations to apply.

Infectious complications in patients with chronic lymphocytic leukemia treated with bruton’s tyrosine kinase inhibitors

2021 ◽  
Vol 21 (3) ◽  
pp. 15-27
Author(s):  
Yulia S. Torshina ◽  
Natalia B. Serebryanaya
Keyword(s):  
Clinical Practice ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Scientific Literature ◽  
Infectious Complications ◽  
Lymphocytic Leukemia ◽  
Lymphoproliferative Diseases ◽  
New Class ◽  
Btk Inhibitors

The aim of this study is to analyze the scientific literature data on the frequency and characteristics of infectious complications during the treatment of patients with lymphoproliferative diseases with a new class of drugs, selective inhibitors of Brutons tyrosine kinase (BTK). This work describes the indications for appointing these drugs as well as the participation of BTK in the development and activation of B cells. We have studied the main characteristics of BTK inhibitors used in clinical practice and associated disorders in the activity of off-target tyrosine kinases. The work describes the main types of known infectious complications developing during the treatment with the drugs of this group, the period of their appearance, and characteristic pathogens.

scholarly journals Effect of sialylation on EGFR phosphorylation and resistance to tyrosine kinase inhibition

2015 ◽  
Vol 112 (22) ◽  
pp. 6955-6960 ◽  
Author(s):  
Hsin-Yung Yen ◽  
Ying-Chih Liu ◽  
Nai-Yu Chen ◽  
Chia-Feng Tsai ◽  
Yi-Ting Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Cancer Progression ◽  
Conformational Changes ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Kinase Activation ◽  
Downstream Signaling ◽  
Egfr Mutant

Epidermal growth factor receptor (EGFR) is a heavily glycosylated transmembrane receptor tyrosine kinase. Upon EGF-binding, EGFR undergoes conformational changes to dimerize, resulting in kinase activation and autophosphorylation and downstream signaling. Tyrosine kinase inhibitors (TKIs) have been used to treat lung cancer by inhibiting EGFR phosphorylation. Previously, we demonstrated that EGFR sialylation suppresses its dimerization and phosphorylation. In this report, we further investigated the effect of sialylation on the phosphorylation profile of EGFR in TKI-sensitive and TKI-resistant cells. Sialylation was induced in cancer progression to inhibit the association of EGFR with EGF and the subsequent autophosphorylation. In the absence of EGF the TKI-resistant EGFR mutant (L858R/T790M) had a higher degree of sialylation and phosphorylation at Y1068, Y1086, and Y1173 than the TKI-sensitive EGFR. In addition, although sialylation in the TKI-resistant mutants suppresses EGFR tyrosine phosphorylation, with the most significant effect on the Y1173 site, the sialylation effect is not strong enough to stop cancer progression by inhibiting the phosphorylation of these three sites. These findings were supported further by the observation that the L858R/T790M EGFR mutant, when treated with sialidase or sialyltransferase inhibitor, showed an increase in tyrosine phosphorylation, and the sensitivity of the corresponding resistant lung cancer cells to gefitinib was reduced by desialylation and was enhanced by sialylation.

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