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Functional Characterization of FLT3 Receptor Signaling Deregulation in Acute Myeloid Leukemia by Single Cell Network Profiling (SCNP)  [PDF]
David B. Rosen,Mark D. Minden,Steven M. Kornblau,Aileen Cohen,Urte Gayko,Santosh Putta,John Woronicz,Erik Evensen,Wendy J. Fantl,Alessandra Cesano
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013543
Abstract: Molecular characterization of the FMS-like tyrosine kinase 3 receptor (FLT3) in cytogenetically normal acute myeloid leukemia (AML) has recently been incorporated into clinical guidelines based on correlations between FLT3 internal tandem duplications (FLT3-ITD) and decreased disease-free and overall survival. These mutations result in constitutive activation of FLT3, and FLT3 inhibitors are currently undergoing trials in AML patients selected on FLT3 molecular status. However, the transient and partial responses observed suggest that FLT3 mutational status alone does not provide complete information on FLT3 biological activity at the individual patient level. Examination of variation in cellular responsiveness to signaling modulation may be more informative.
Neurotrophin-3 and FLT3 Tyrosine Kinase Receptor in Perinatal Life  [PDF]
Ariadne Malamitsi-Puchner,Emmanouel Economou,Theodora Boutsikou,Konstantinos E. Nikolaou,Nikolaos Vrachnis
Mediators of Inflammation , 2005, DOI: 10.1155/mi.2005.53
Abstract: Our aim is to determine—in 30 healthy full-term infants and their mothers—circulating levels of neurotrophin-3 (NT-3) (important for antenatal and postnatal brain development and implicated in the immune response) and FLT3 tyrosine kinase receptor (FLT3) (controlling hematopoiesis and found in the nervous tissue), in the fetal and neonatal life. NT-3 levels, in contrast to FLT3 ones, increased significantly on the fourth postnatal day in relation to the low levels found in the mother, fetus, and day 1 neonate (P=.03, respectively). Maternal and umbilical NT3 levels positively correlated with respective FLT3 levels (P=.003 and P=.03). Circulating NT-3 levels increased in early neonatal life, possibly due to exposure to various stimuli soon after birth. FLT3 levels do not seem to behave accordingly, although these two substances probably synergize.
An overview on the role of FLT3-tyrosine kinase receptor in acute myeloid leukemia: biology and treatment
Tiziana Grafone,Michela Palmisano,Chiara Nicci,Sergio Storti
Oncology Reviews , 2012, DOI: 10.4081/oncol.2012.e8
Abstract: Hematopoiesis, the process by which the hematopoietic stem cells and progenitors differentiate into blood cells of various lineages, involves complex interactions of transcription factors that modulate the expression of downstream genes and mediate proliferation and differentiation signals. Despite the many controls that regulate hematopoiesis, mutations in the regulatory genes capable of promoting leukemogenesis may occur. The FLT3 gene encodes a tyrosine kinase receptor that plays a key role in controlling survival, proliferation and differentiation of hematopoietic cells. Mutations in this gene are critical in causing a deregulation of the delicate balance between cell proliferation and differentiation. In this review, we provide an update on the structure, synthesis and activation of the FLT3 receptor and the subsequent activation of multiple downstream signaling pathways. We also review activating FLT3 mutations that are frequently identified in acute myeloid leukemia, cause activation of more complex downstream signaling pathways and promote leukemogenesis. Finally, FLT3 has emerged as an important target for molecular therapy. We, therefore, report on some recent therapies directed against it.
Functional Pathway Analysis Using SCNP of FLT3 Receptor Pathway Deregulation in AML Provides Prognostic Information Independent from Mutational Status  [PDF]
Alessandra Cesano, Santosh Putta, David B. Rosen, Aileen C. Cohen, Urte Gayko, Kavita Mathi, John Woronicz, Rachael E. Hawtin, Larry Cripe, Zhuoxin Sun, Martin S. Tallman, Elisabeth Paietta
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0056714
Abstract: FMS-like tyrosine kinase 3 receptor (FLT3) internal tandem duplication (ITD) mutations result in constitutive activation of this receptor and have been shown to increase the risk of relapse in patients with acute myeloid leukemia (AML); however, substantial heterogeneity in clinical outcomes still exists within both the ITD mutated and unmutated AML subgroups, suggesting alternative mechanisms of disease relapse not accounted by FLT3 mutational status. Single cell network profiling (SCNP) is a multiparametric flow cytometry based assay that simultaneously measures, in a quantitative fashion and at the single cell level, both extracellular surface marker levels and changes in intracellular signaling proteins in response to extracellular modulators. We previously reported an initial characterization of FLT3 ITD-mediated signaling using SCNP. Herein SCNP was applied sequentially to two separate cohorts of samples collected from elderly AML patients at diagnosis. In the first (training) study, AML samples carrying unmutated, wild-type FLT3 (FLT3 WT) displayed a wide range of induced signaling, with a fraction having signaling profiles comparable to FLT3 ITD AML samples. Conversely, the FLT3 ITD AML samples displayed more homogeneous induced signaling, with the exception of patients with low (<40%) mutational load, which had profiles comparable to FLT3 WT AML samples. This observation was then confirmed in an independent (verification) cohort. Data from the second cohort were also used to assess the association between SCNP data and disease-free survival (DFS) in the context of FLT3 and nucleophosmin (NPM1) mutational status among patients who achieved complete remission (CR) to induction chemotherapy. The combination of SCNP read outs together with FLT3 and NPM1 molecular status improved the DFS prediction accuracy of the latter. Taken together, these results emphasize the value of comprehensive functional assessment of biologically relevant signaling pathways in AML as a basis for the development of highly predictive tests for guidance of post-remission therapy.
Ergodicity of polygonal slap maps  [PDF]
Gianluigi Del Magno,Jo?o Lopes Dias,Pedro Duarte,José Pedro Gaiv?o
Mathematics , 2013, DOI: 10.1088/0951-7715/27/8/1969
Abstract: Polygonal slap maps are piecewise affine expanding maps of the interval obtained by projecting the sides of a polygon along their normals onto the perimeter of the polygon. These maps arise in the study of polygonal billiards with non-specular reflections laws. We study the absolutely continuous invariant probabilities of the slap maps for several polygons, including regular polygons and triangles. We also present a general method for constructing polygons with slap maps having more than one ergodic absolutely continuous invariant probability.
A Dimer of the Toll-Like Receptor 4 Cytoplasmic Domain Provides a Specific Scaffold for the Recruitment of Signalling Adaptor Proteins  [PDF]
Ricardo Nú?ez Miguel, Joyce Wong, Julian F. Westoll, Heather J. Brooks, Luke A. J. O'Neill, Nicholas J. Gay, Clare E. Bryant, Tom P. Monie
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0000788
Abstract: The Toll-like receptor 4 (TLR4) is a class I transmembrane receptor expressed on the surface of immune system cells. TLR4 is activated by exposure to lipopolysaccharides derived from the outer membrane of Gram negative bacteria and forms part of the innate immune response in mammals. Like other class 1 receptors, TLR4 is activated by ligand induced dimerization, and recent studies suggest that this causes concerted conformational changes in the receptor leading to self association of the cytoplasmic Toll/Interleukin 1 receptor (TIR) signalling domain. This homodimerization event is proposed to provide a new scaffold that is able to bind downstream signalling adaptor proteins. TLR4 uses two different sets of adaptors; TRAM and TRIF, and Mal and MyD88. These adaptor pairs couple two distinct signalling pathways leading to the activation of interferon response factor 3 (IRF-3) and nuclear factor κB (NFκB) respectively. In this paper we have generated a structural model of the TLR4 TIR dimer and used molecular docking to probe for potential sites of interaction between the receptor homodimer and the adaptor molecules. Remarkably, both the Mal and TRAM adaptors are strongly predicted to bind at two symmetry-related sites at the homodimer interface. This model of TLR4 activation is supported by extensive functional studies involving site directed mutagenesis, inhibition by cell permeable peptides and stable protein phosphorylation of receptor and adaptor TIR domains. Our results also suggest a molecular mechanism for two recent findings, the caspase 1 dependence of Mal signalling and the protective effects conferred by the Mal polymorphism Ser180Leu.
Estradiol Binds to Insulin and Insulin Receptor Decreasing Insulin Binding in vitro  [PDF]
Robert Root-Bernstein,Patrick F. Dillon
Frontiers in Endocrinology , 2014, DOI: 10.3389/fendo.2014.00118
Abstract: Rationale: Insulin (INS) resistance associated with hyperestrogenemias occurs in gestational diabetes mellitus, polycystic ovary syndrome, ovarian hyperstimulation syndrome, estrogen therapies, metabolic syndrome, and obesity. The mechanism by which INS and estrogen interact is unknown. We hypothesize that estrogen binds directly to INS and the insulin receptor (IR) producing INS resistance.
Molecular Analysis of the Prostacyclin Receptor’s Interaction with the PDZ1 Domain of Its Adaptor Protein PDZK1  [PDF]
Gabriel Birrane, Eamon P. Mulvaney, Rinku Pal, B. Therese Kinsella, Olivier Kocher
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053819
Abstract: The prostanoid prostacyclin, or prostaglandin I2, plays an essential role in many aspects of cardiovascular disease. The actions of prostacyclin are mainly mediated through its activation of the prostacyclin receptor or, in short, the IP. In recent studies, the cytoplasmic carboxy-terminal domain of the IP was shown to bind several PDZ domains of the multi-PDZ adaptor PDZK1. The interaction between the two proteins was found to enhance cell surface expression of the IP and to be functionally important in promoting prostacyclin-induced endothelial cell migration and angiogenesis. To investigate the interaction of the IP with the first PDZ domain (PDZ1) of PDZK1, we generated a nine residue peptide (KK411IAACSLC417) containing the seven carboxy-terminal amino acids of the IP and measured its binding affinity to a recombinant protein corresponding to PDZ1 by isothermal titration calorimetry. We determined that the IP interacts with PDZ1 with a binding affinity of 8.2 μM. Using the same technique, we also determined that the farnesylated form of carboxy-terminus of the IP does not bind to PDZ1. To understand the molecular basis of these findings, we solved the high resolution crystal structure of PDZ1 bound to a 7-residue peptide derived from the carboxy-terminus of the non-farnesylated form of IP (411IAACSLC417). Analysis of the structure demonstrates a critical role for the three carboxy-terminal amino acids in establishing a strong interaction with PDZ1 and explains the inability of the farnesylated form of IP to interact with the PDZ1 domain of PDZK1 at least in vitro.
qPCR in gastrointestinal stromal tumors: Evaluation of reference genes and expression analysis of KIT and the alternative receptor tyrosine kinases FLT3, CSF1-R, PDGFRB, MET and AXL
Jana Fassunke, Marie-Christine Blum, Hans-Ulrich Schildhaus, Marc Zapatka, Benedikt Brors, Helen Künstlinger, Reinhard Büttner, Eva Wardelmann, Sabine Merkelbach-Bruse
BMC Molecular Biology , 2010, DOI: 10.1186/1471-2199-11-100
Abstract: Gene expression variability of the pooled cDNA samples is much lower than the single reverse transcription cDNA synthesis. By combining the lowest variability values of fixed and fresh tissue, the genes POLR2A, PPIA, RPLPO and TFRC were chosen for further analysis of the GIST samples. Overexpression of KIT compared to the corresponding normal tissue was detected in each GIST subgroup except in GIST with PDGFRA exon 18 mutation. Comparing our sample groups, no significant differences in the gene expression levels of FLT3, CSF1R and AXL were determined. An exception was the sample group with KIT exon 9 mutation. A significantly reduced expression of CSF1R, FLT3 and PDGFRB compared to the normal tissue was detected. GIST with mutations in KIT exon 9 and 11 and in PDGFRA exon 18 showed a significant PDGFRB downregulation.As the variability of expression levels for the reference genes is very high comparing fresh frozen and formalin-fixed tissue there is a strong need for validation in each tissue type. None of the alternative receptor tyrosine kinases analyzed is associated with the pathogenesis of wild-type or mutated GIST. It remains to be clarified whether an autocrine or paracrine mechanism by overexpression of receptor tyrosine kinase ligands is responsible for the tumorigenesis of wt-GIST.Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract and are characterized by the expression of the KIT receptor (stem cell factor receptor, CD117) and to a lesser extent of PDGFRA (platelet derived growth factor receptor alpha), representing two closely related receptor tyrosine kinases (RTK) [1,2]. The majority of GIST shows oncogenic mutations either in KIT or PDGFRA [3,4]. Mainly, mutations in exon 9 or 11 of the KIT gene or in exon 18 of PDGFRA lead to ligand independent, constitutive activation of the kinase function [5]. About 60% of all GIST carry an exon 11 mutation of KIT which encodes the juxtamembrane domain of th
FLT3 mutations in canine acute lymphocytic leukemia
Steven E Suter, George W Small, Eric L Seiser, Rachael Thomas, Matthew Breen, Kristy L Richards
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-38
Abstract: We molecularly characterized FLT3 mutations in two dogs and one cell line, by DNA sequencing, gene expression analysis via quantitative real-time PCR, and sensitivity to the FLT3 inhibitor lestaurtinib via in vitro proliferation assays. FLT 3 and downstream mediators of FLT3 activation were assessed by Western blotting.The canine B-cell leukemia cell line, GL-1, and neoplastic cells from 2/7 dogs diagnosed cytologically with ALL were found to have FLT3 ITD mutations and FLT3 mRNA up-regulation. Lestaurtinib, a small molecule FLT3 inhibitor, significantly inhibited the growth of GL-1 cells, while not affecting the growth of two other canine lymphoid cell lines without the FLT3 mutation. Finally, western blots were used to confirm the conserved downstream mediators of FLT3 activating mutations.These results show that ALL and FLT3 biology is conserved between canine and human patients, supporting the notion that canine ALL, in conjunction with the GL-1 cell line, will be useful in the development of a relevant large animal model to aid in the study of human FLT3 mutant leukemias.FMS-like tyrosine kinase 3 (FLT3), one of the most commonly mutated genes in human leukemias, is a class III receptor tyrosine kinase that is an important regulatory gene involved in normal hematopoiesis [1,2]. FLT3 is expressed predominantly on myeloid and lymphoid hematopoietic progenitors, where the receptor, once bound by its cognate ligand (FLT3 ligand, FL), activates a variety of downstream targets. These include proteins in the signal transducers and activators of transcription (STAT), mitogen-activated protein (MAP) kinase, and AKT pathways that are all involved in regulating proliferation, differentiation, and cell survival [1,2]. In vitro studies have shown that constitutively activated FLT3 triggers downstream signaling pathways resulting in continuous cellular proliferation and resistance to apoptotic cell death. Constitutively activated FLT3 occurs via two main mechanisms: coexpres
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