DOCSLIB.ORG

Activating FLT3 Mutations Are Detectable in Chronic and Blast Phases of Chronic Myeloproliferative Disorders Other Than Chronic Myeloid Leukemia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Activating FLT3 Mutations Are Detectable in Chronic and Blast Phases of Chronic Myeloproliferative Disorders Other Than Chronic Myeloid Leukemia Hematopathology / FLT3 IN CHRONIC MYELOPROLIFERATIVE DISORDERS Activating FLT3 Mutations Are Detectable in Chronic and Blast Phases of Chronic Myeloproliferative Disorders Other Than Chronic Myeloid Leukemia Pei Lin, MD, Dan Jones, MD, PhD, L. Jeffrey Medeiros, MD, Weina Chen, MD, PhD, Francisco Vega-Vazquez, MD, PhD, and Rajyalakshmi Luthra, PhD Key Words: FLT3 gene mutations; Chronic myeloproliferative disorders Downloaded from https://academic.oup.com/ajcp/article/126/4/530/1759842 by guest on 30 September 2021 DOI: 10.1309/JT5BE2L1FGG8P8Y6 Abstract FLT3 (CD135) is a member of the class III receptor tyro- FLT3 gene mutations, either internal tandem sine kinase family that is expressed by early hematopoietic duplication (ITD) or D835 point mutations, have been progenitors. It is composed of 5 immunoglobulin-like studied extensively in acute myeloid leukemia and domains in the extracellular region, a single transmembrane myelodysplastic syndrome (MDS). Little is known about sequence, and intracellularly, a short juxtamembrane portion FLT3 mutations in chronic myeloproliferative diseases followed by an interrupted kinase domain.1 (CMPDs) or their relationship with V617F JAK2 Two distinct types of activating mutations of the FLT3 mutations. We analyzed bone marrow samples from 142 gene are most common. An internal tandem duplication (ITD) patients with Philadelphia (Ph) chromosome– CMPD resulting from duplication of the juxtamembrane portion of or CMPD/MDS and from 119 patients with Ph+ the gene occurs in up to 20% of acute myeloid leukemia chronic myeloid leukemia (CML) using a multiplex (AML) and 3% of myelodysplastic syndrome (MDS) cases. A polymerase chain reaction assay. FLT3 mutations, 11 missense point mutation of codon 835, or less commonly ITD and 2 D835, were detected in 13 (9.2%) patients codon 836, involves the activation loop of the FLT3 protein. with CMPD or CMPD/MDS, 7 in blast phase and 6 in These point mutations, collectively referred to here as D835, chronic phase. Analyses for JAK2 mutations in 11 of 13 occur in up to 7% of AML and 3% of MDS cases. Both muta- cases were all negative. By contrast, no FLT3 mutations tions result in constitutive activation of FLT3 kinase by were detected in CML, including 108 chronic and 11 autophosphorylation.1,2 blast phase cases. FLT3 mutations occur in Although FLT3/ITD mutations can induce myeloprolifer- approximately 10% of CMPD and CMPD/MDS but are ative diseases in a transgenic mouse model,3 FLT3 mutations not observed in JAK2+ CMPD or in CML. have been demonstrated mainly in patients with AML or MDS.1,4-6 The mutations are more common in AML with monocytic differentiation, and their presence, especially ITD, is associated with marked leukocytosis and a high risk for relapse. FLT3 mutations also are implicated in leukemic trans- formation of MDS.1,7 Rare cases of acute lymphoblastic leukemia with FLT3 gene mutations reported are primarily cases associated with MLL gene alterations.8,9 Studies of FLT3 mutations in chronic myeloproliferative diseases (CMPDs) or CMPD/MDS, in blast or chronic phase, are extremely rare. Yokota and colleagues6 studied 20 patients with chronic myelogenous leukemia (CML) and found no mutations. In another study, Pardanani and colleagues10 found 530 Am J Clin Pathol 2006;126:530-533 © American Society for Clinical Pathology 530 DOI: 10.1309/JT5BE2L1FGG8P8Y6 Hematopathology / ORIGINAL ARTICLE no FLT3 mutations in 115 patients with a variety of CMPDs, CA), forward primers for ITD and D835 were labeled with a including 48 with myelofibrosis with myeloid metaplasia, 21 fluorescent dye, 6-carboxyfluorescein (FAM).16 The presence with polycythemia vera, 20 with essential thrombocythemia, of any PCR fragment larger than the wild-type allele was con- 16 with systemic mast cell disease, 4 with hypereosinophilic sidered positive for ITD. D835 PCR products were digested syndrome, 3 with chronic neutrophilic leukemia, and 3 with with the EcoRV restriction enzyme before capillary elec- myelodysplastic syndrome. trophoresis. The wild-type allele cut by this enzyme resulted Mutation in codon 617 of the JH2 domain of Janus kinase in 2 fragments of 64 and 48 base pairs. In contrast, mutations 2 (JAK2) is the most common molecular abnormality found in at D835 alter the EcoRV recognition site and result in one Philadelphia chromosome (Ph)– CMPD, especially poly- 112-base-pair fragment. The sensitivity of these assays is cythemia vera (70%-80%), essential thrombocythemia (40%- approximately 2%, ie, 1 mutated cell in 50 total cells, as estab- 50%), and chronic idiopathic myelofibrosis (30%-50%), as lished by dilutional studies. Downloaded from https://academic.oup.com/ajcp/article/126/4/530/1759842 by guest on 30 September 2021 well as a small number of myelodysplastic syndromes and To detect V617F JAK2 gene mutations, DNA isolated atypical myeloid disorders (7%).11,12 The relationship from bone marrow aspirate and/or core biopsy specimens was between FLT3/ITD or FLT3/D835 and JAK2 mutation in Ph– amplified using forward primer 5'-TCT TTC TTT GAA GCA CMPD has been rarely explored. GCA AGT ATG AT-3' and biotin-labeled reverse primer 5'- To assess the prevalence of FLT3 mutations in CMPD or ACA AAA ACA GAT GCT CTG AGA AAG G-3'. A single- CMPD/MDS, we reviewed bone marrow aspirate samples stranded biotinylated template strand was prepared for obtained from patients with these diseases and analyzed for sequencing using the Pyrosequencing Vacuum Prep Tool FLT3 mutations by a polymerase chain reaction (PCR) assay (Biotage, Uppsala, Sweden). Pyrosequencing reactions were at our institution. All cases assessed were Ph–, confirmed by performed on a PSQ HS 96 instrument using a JAK2 sequenc- conventional cytogenetics and molecular studies. We also ana- ing primer, 5'-ATT ATG GAG TAT GT-3'.11,12,17 All primers lyzed the corresponding bone marrow samples of 11 patients were obtained from Invitrogen, Carlsbad, CA, and analyses with FLT3 mutation–positive CMPD or CMPD/MDS for the were performed using appropriate negative and positive con- JAK2 V617F mutation. For comparison, we assessed a large trol samples. The sensitivity of detection is approximately number of cases of Ph+ CML. In a subset of cases, we retro- 10%, ie, 1 mutated cell in 10 total cells. spectively analyzed archived, formalin-fixed, paraffin-embed- For archived, formalin-fixed, paraffin-embedded bone ded bone marrow clot samples acquired previously to deter- marrow clot samples, DNA was extracted using the QIAamp mine when the mutations became detectable during the course tissue kit (QIAGEN, Hilden, Germany) according to the man- of disease. ufacturer’s instructions. Subsequent analysis followed the same procedures described for fresh samples. In a few cases, fresh and corresponding archived samples were analyzed and compared to ensure quality. Materials and Methods The clinical history and pathologic diagnosis of each The files of the Molecular Diagnostics Laboratory, patient were reviewed independently and verified by 2 Department of Hematopathology, at our hospital were hematopathologists. Clinical data were obtained by review of searched for all CMPD cases that were analyzed for FLT3 medical records. The peripheral blood smears, Wright- gene mutations from March 1999 to August 2003. The World Giemsa–stained bone marrow aspirate smears, and H&E- Health Organization classification of hematopoietic neo- stained bone marrow biopsy sections of cases with FLT3 plasms was used for diagnosis,13 with unclassifiable cases mutations were reviewed. Conventional cytogenetic analysis showing myeloproliferative and dysplastic features diagnosed was performed on bone marrow aspirate material using meth- as CMPD/MDS. ods previously described.18 A multiplex fluorescent-based PCR method was used to detect ITD and D835 point mutations in FLT3. DNA was iso- lated from bone marrow aspirate samples by using a standard Results phenol-chloroform extraction method. The presence of ITD was assessed by amplification of the juxtamembrane domain From March 1999 to August 2003, 1,978 consecutive using primers from exons 11 and 12 as described by Kiyoi and bone marrow aspirate samples from 1,167 patients with a vari- Naoe.14 The presence of D835 point mutations was assessed ety of acute and chronic myeloid and lymphoid disorders were by a restriction fragment length polymorphism–mediated analyzed for FLT3 mutations. Among them, 165 samples were assay using primers flanking the mutation site.15 To facilitate obtained from 142 patients with Ph– CMPD or CMPD/MDS, the detection of PCR products by capillary electrophoresis on including chronic (n = 47) or blastic (n = 16) phase of CMPD a 3100 genetic analyzer (Applied Biosystems, Foster City, other than CML, blast (n = 34) or chronic (n = 39) phase of © American Society for Clinical Pathology Am J Clin Pathol 2006;126:530-533 531 531 DOI: 10.1309/JT5BE2L1FGG8P8Y6 531 Lin et al / FLT3 IN CHRONIC MYELOPROLIFERATIVE DISORDERS chronic myelomonocytic leukemia (CMML), and samples from 5 cases obtained during the chronic phase CMPD/MDS, unclassifiable (n = 6). We also analyzed bone were analyzed for FLT3 mutations, 4 CMPD, unclassifiable marrow samples from 119 patients with CML in chronic or and 1 chronic idiopathic myelofibrosis. The number of sam- blast phase that were confirmed by conventional cytogenetic ples assessed ranged from 1 to 4 in each case, and the blast or molecular studies. Cases of CMML in blast phase were counts ranged from 1% to 8% per sample. FLT3/ITD mutation excluded from final analysis because it is difficult to distin- was detected in 2 CMPD, unclassifiable with 6% of blasts in guish underlying CMML from MDS. the bone marrow aspirate in each. Results were negative in FLT3 mutations were detected in 15 bone marrow aspi- other samples. rate specimens from 13 patients (9.2%) diagnosed with Ph– CMPD or CMPD/MDS. They were ITD in 11 cases and D835 point mutation in 2 cases. FLT3 mutations were not detected Discussion Downloaded from https://academic.oup.com/ajcp/article/126/4/530/1759842 by guest on 30 September 2021 in any of the 119 cases of CML, including 108 in chronic phase and 11 in blast phase.
Load more

Recommended publications
  • Promoter Janus Kinase 3 Proximal Characterization and Analysis Of
    The Journal of Immunology Characterization and Analysis of the Proximal Janus Kinase 3 Promoter1 Martin Aringer,2*† Sigrun R. Hofmann,2* David M. Frucht,* Min Chen,* Michael Centola,* Akio Morinobu,* Roberta Visconti,* Daniel L. Kastner,* Josef S. Smolen,† and John J. O’Shea3* Janus kinase 3 (Jak3) is a nonreceptor tyrosine kinase essential for signaling via cytokine receptors that comprise the common ␥-chain (␥c), i.e., the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Jak3 is preferentially expressed in hemopoietic cells and is up-regulated upon cell differentiation and activation. Despite the importance of Jak3 in lymphoid development and immune function, the mechanisms that govern its expression have not been defined. To gain insight into this issue, we set out to characterize the Jak3 promoter. The 5؅-untranslated region of the Jak3 gene is interrupted by a 3515-bp intron. Upstream of this intron and the transcription initiation site, we identified an ϳ1-kb segment that exhibited lymphoid-specific promoter activity and was responsive to TCR signals. Truncation of this fragment revealed that core promoter activity resided in a 267-bp fragment that contains putative Sp-1, AP-1, Ets, Stat, and other binding sites. Mutation of the AP-1 sites significantly diminished, whereas mutation of the Ets sites abolished, the inducibility of the promoter construct. Chromatin immunoprecipitation assays showed that histone acetylation correlates with mRNA expression and that Ets-1/2 binds this region. Thus, transcription factors that bind these sites, especially Ets family members, are likely to be important regulators of Jak3 expression.
    [Show full text]
  • Biomarker Testing in Non- Small Cell Lung Cancer (NSCLC)
    The biopharma business of Merck KGaA, Darmstadt, Germany operates as EMD Serono in the U.S. and Canada. Biomarker testing in non- small cell lung cancer (NSCLC) Copyright © 2020 EMD Serono, Inc. All rights reserved. US/TEP/1119/0018(1) Lung cancer in the US: Incidence, mortality, and survival Lung cancer is the second most common cancer diagnosed annually and the leading cause of mortality in the US.2 228,820 20.5% 57% Estimated newly 5-year Advanced or 1 survival rate1 metastatic at diagnosed cases in 2020 diagnosis1 5.8% 5-year relative 80-85% 2 135,720 survival with NSCLC distant disease1 Estimated deaths in 20201 2 NSCLC, non-small cell lung cancer; US, United States. 1. National Institutes of Health (NIH), National Cancer Institute. Cancer Stat Facts: Lung and Bronchus Cancer website. www.seer.cancer.gov/statfacts/html/lungb.html. Accessed May 20, 2020. 2. American Cancer Society. What is Lung Cancer? website. https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html. Accessed May 20, 2020. NSCLC is both histologically and genetically diverse 1-3 NSCLC distribution by histology Prevalence of genetic alterations in NSCLC4 PTEN 10% DDR2 3% OTHER 25% PIK3CA 12% LARGE CELL CARCINOMA 10% FGFR1 20% SQUAMOUS CELL CARCINOMA 25% Oncogenic drivers in adenocarcinoma Other or ADENOCARCINOMA HER2 1.9% 40% KRAS 25.5% wild type RET 0.7% 55% NTRK1 1.7% ROS1 1.7% Oncogenic drivers in 0% 20% 40% 60% RIT1 2.2% squamous cell carcinoma Adenocarcinoma DDR2 2.9% Squamous cell carcinoma NRG1 3.2% Large cell carcinoma
    [Show full text]
  • Kinase Inhibitors: an Introduction
    David Peters Baran Group Meeting Kinase Inhibitors: An Introduction 2/2/19 INTRODUCTION SIGNAL TRANSDUCTION KINASES ARE IMPORTANT IN HUMAN BIOLOGY/DISEASE: The process describing how a signal (chemical/physical) is transmitted through a - Kinases are a superfamily of proteins (5th largest in humans) cell ultimately resulting in a cellular response - 518 genes and 106 pseudogenes - Diverse in size, subunit structure, and cellular location RECEPTOR TRANSDUCERS EFFECTORS - ~260 residues make up their conserved catalytic core - dysregulation of kinases occurs in many diseases (cancer, inflamatory, degenerative, and autoimmune diseases) - signals can originate inside or outside the cell - 244 of the 518 map to disease loci - signals generally passed through a series of steps (signal transduction pathway) often consisting of multiple enzymes and messengers protein O - pathways open possibility for signal aplification (>1x106) kinase ATP + PROTEIN OH ADP + PROTEIN O P O - Extracellular signals transduced by RTKs, GPCR’s, guanlyl cyclases, or ligand-gated Ion channels O - Phosphorylation is the most prominent covalent modification/signal in KINASES INHIBITORS ARE IMPORTANT IN DISEASE THERAPY/RESEARCH: cellular regulation - currently 51 FDA approved small molecule kinase inhibitors - “converter enzymes” (protein kinases and phosphoprotein phosphorlyases) - 4 FDA approved antibody kinase inhibitors are regulated; conserve ATP/maintain desired target protein state - thousands of known inhibitors spanning the kinome - pathway ends by affecting biomolecule
    [Show full text]
  • The Role of Signaling Pathways in the Development and Treatment of Hepatocellular Carcinoma
    Oncogene (2010) 29, 4989–5005 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc REVIEW The role of signaling pathways in the development and treatment of hepatocellular carcinoma S Whittaker1,2, R Marais3 and AX Zhu4 1Dana-Farber Cancer Institute, Boston, MA, USA; 2The Broad Institute, Cambridge, MA, USA; 3Institute of Cancer Research, London, UK and 4Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA Hepatocellular carcinoma (HCC) is a highly prevalent, malignancy in adults (Pons-Renedo and Llovet, 2003). treatment-resistant malignancy with a multifaceted mole- For the vast majority of patients, HCC is a late cular pathogenesis. Current evidence indicates that during complication of chronic liver disease, and as such, is hepatocarcinogenesis, two main pathogenic mechanisms often associated with cirrhosis. The main risk factors for prevail: (1) cirrhosis associated with hepatic regeneration the development of HCC include infection with hepatitis after tissue damage caused by hepatitis infection, toxins B virus (HBV) or hepatitis C virus (HCV). Hepatitis (for example, alcohol or aflatoxin) or metabolic influ- infection is believed to be the main etiologic factor in ences, and (2) mutations occurring in single or multiple 480% of cases (Anzola, 2004). Other risk factors oncogenes or tumor suppressor genes. Both mechanisms include excessive alcohol consumption, nonalcoholic have been linked with alterations in several important steatohepatitis, autoimmune hepatitis, primary biliary cellular signaling pathways. These pathways are of cirrhosis, exposure to environmental carcinogens (parti- interest from a therapeutic perspective, because targeting cularly aflatoxin B) and the presence of various genetic them may help to reverse, delay or prevent tumorigenesis.
    [Show full text]
  • Epigenetic Gene Regulation by Janus Kinase 1 in Diffuse Large B-Cell Lymphoma
    Epigenetic gene regulation by Janus kinase 1 in diffuse large B-cell lymphoma Lixin Ruia,b,c,1,2, Amanda C. Drennanb,c,1, Michele Ceribellia,1, Fen Zhub,c, George W. Wrightd, Da Wei Huanga, Wenming Xiaoe, Yangguang Lib,c, Kreg M. Grindleb,c,LiLub,c, Daniel J. Hodsona, Arthur L. Shaffera, Hong Zhaoa, Weihong Xua, Yandan Yanga, and Louis M. Staudta,2 aLymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892; bDepartment of Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705; cCarbone Cancer Center, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705; dBiometric Research Branch, DCTD, National Cancer Institute, NIH, Bethesda, MD 20892; and eDivision of Bioinformatics and Biostatistics, National Center for Toxicological Research/Food and Drug Administration, Jefferson, AR 72079 Contributed by Louis M. Staudt, September 29, 2016 (sent for review July 22, 2016; reviewed by Anthony R. Green and Ross L. Levine) Janus kinases (JAKs) classically signal by activating STAT transcription promote STAT dimerization, nuclear translocation, and binding factors but can also regulate gene expression by epigenetically to cis-regulatory elements to regulate transcription (15, 17). This phosphorylating histone H3 on tyrosine 41 (H3Y41-P). In diffuse large canonical JAK/STAT pathway is deregulated in several hemato- B-cell lymphomas (DLBCLs), JAK signaling is a feature of the activated logic malignancies (16). In DLBCL, STAT3 is activated in the B-cell (ABC) subtype and is triggered by autocrine production of IL-6 ABC subtype and regulates gene expression to promote the sur- and IL-10.
    [Show full text]
  • JAK3 Deficiency, (SCID T-B+)
    JAK3 deficiency, (SCID T-B+) Author: Professor Luigi D. Notarangelo1,2 Creation Date: November 2001 Update: January 2005 1member of the European editorial committee of Orphanet encyclopedia 2Department of Pediatrics, University of Brescia, Spedali Civil, 25123 Brescia, Italy. [email protected] Abstract Keywords Diagnosis criteria/definition Differential diagnosis Prevalence Clinical description Treatment Etiology Diagnostic methods Genetic counseling Antenatal diagnosis Unresolved questions References Abstract JAK3 (Janus Kinase 3) deficiency is an autosomal recessive form of severe combined immune deficiency (SCID). It is characterized by lack of circulating T and NK (Natural Killer) cells and normal number of B lymphocytes. The disease is due to mutations in the JAK3 gene encoding an intracellular tyrosine kinase that is physically and functionally coupled with several cytokine receptors. Identification of gene anomalies has allowed physicians to make the diagnosis (even prenatal), and may prompt novel forms of treatment based on gene therapy. Although a relatively low number of JAK3-deficient subjects have been diagnosed, JAK3 deficiency represents an important cause of autosomal recessive SCID in the United States and its prevalence in Europe appears to be even higher. However it is considered as a rare disease (incidence is between 1/100,000 and 1/1,000,000 live births). JAK3-deficient patients present with the classical clinical features of SCID in the first few months of life, i.e. chronic diarrhea, failure to thrive, recurrent respiratory infection and/or generalized infections from opportunistic pathogens, or signs of graft-versus-host reaction (skin rash, abnormalities of liver function, pancytopenia) from transplacental acquired maternal T cells.
    [Show full text]
  • Advances in Systemic Therapy for HER2-Positive Metastatic Breast Cancer Phuong Khanh H Morrow1, Francisco Zambrana1,2 and Francisco J Esteva1
    Available online http://breast-cancer-research.com/content/11/4/207 Review Advances in systemic therapy for HER2-positive metastatic breast cancer Phuong Khanh H Morrow1, Francisco Zambrana1,2 and Francisco J Esteva1 1Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Holcombe Boulevard, Houston, TX 77030, USA 2Current address: Department of Medical Oncology, Hospital Infanta Sofia, Paseo de Europa, 34, Madrid 28702, Spain Corresponding author: Phuong Khanh H Morrow, [email protected] Published: 15 July 2009 Breast Cancer Research 2009, 11:207 (doi:10.1186/bcr2324) This article is online at http://breast-cancer-research.com/content/11/4/207 © 2009 BioMed Central Ltd Abstract differentiation, survival, and migration that are associated with Human epidermal growth factor receptor (HER)2 over-expression HER2-positive breast cancers (Figure 1). Thus, women with is associated with a shortened disease-free interval and poor HER2-positive breast cancers exhibit significantly decreased survival. Although the addition of trastuzumab to chemotherapy in disease-free survival and overall survival (OS) [2-5]. the first-line setting has improved response rates, progression-free survival, and overall survival, response rates declined when trastu- This review discusses progress in the treatment of HER2- zumab was used beyond the first-line setting because of multiple positive metastatic breast cancer since the discovery of the mechanisms of resistance. Studies have demonstrated the clinical utility of continuing
    [Show full text]
  • Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia
    cancers Review Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia Kalpana K. Bhanumathy 1,*, Amrutha Balagopal 1, Frederick S. Vizeacoumar 2 , Franco J. Vizeacoumar 1,3, Andrew Freywald 2 and Vincenzo Giambra 4,* 1 Division of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; [email protected] (A.B.); [email protected] (F.J.V.) 2 Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada; [email protected] (F.S.V.); [email protected] (A.F.) 3 Cancer Research Department, Saskatchewan Cancer Agency, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada 4 Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies (ISBReMIT), Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy * Correspondence: [email protected] (K.K.B.); [email protected] (V.G.); Tel.: +1-(306)-716-7456 (K.K.B.); +39-0882-416574 (V.G.) Simple Summary: Protein phosphorylation is a key regulatory mechanism that controls a wide variety of cellular responses. This process is catalysed by the members of the protein kinase su- perfamily that are classified into two main families based on their ability to phosphorylate either tyrosine or serine and threonine residues in their substrates. Massive research efforts have been invested in dissecting the functions of tyrosine kinases, revealing their importance in the initiation and progression of human malignancies. Based on these investigations, numerous tyrosine kinase inhibitors have been included in clinical protocols and proved to be effective in targeted therapies for various haematological malignancies.
    [Show full text]
  • Targeting Janus Kinase 2 in Her2/Neu-Expressing Mammary Cancer: Implications for Cancer Prevention Andtherapy
    Published OnlineFirst July 28, 2009; DOI: 10.1158/0008-5472.CAN-09-0746 Molecular Biology, Pathobiology, andGenetics Targeting Janus Kinase 2 in Her2/neu-Expressing Mammary Cancer: Implications for Cancer Prevention andTherapy Kazuhito Sakamoto,1 Wan-chi Lin,1 Aleata A. Triplett,1 and Kay-Uwe Wagner1,2 1Eppley Institute for Research in Cancer and Allied Diseases and 2Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska Abstract the Stat5-mediated transcriptional activation of the cyclin D1 The Janus kinase 2 (Jak2) is essential for normal mammary promoter (5). Our own studies using Jak2-deficient mammary gland development, but this tyrosine kinase and its main epithelial cells and their isogenic wild-type controls suggest that effector, signal transducer and activator of transcription 5, are signaling through this Janus kinase controls not only the also active in a significant subset of human breast cancers. We expression of the cyclin D1 mRNA but, more importantly, Jak2 regulates the accumulation of the cyclin D1 protein in the nucleus have recently reported that Jak2 controls the expression and h nuclear accumulation of cyclin D1. Because this particular D- through modification of the Akt1/GSK3 pathway, which type cyclin has been suggested to be a key mediator for ErbB2- mediates the phosphorylation and nuclear export of cyclin D1 associated mammary tumorigenesis, we deleted Jak2 from (6). The notion that cyclin D1 is a key target of the Jak/Stat pathway is supported by the fact that females deficient in cyclin ErbB2-expressing mammary epithelial cells prior to tumor onset and in neoplastic cells to address whether this tyrosine D1 exhibit impaired mammary gland development similar to Jak2 kinase plays a role in the initiation as well as progression of and Stat5 conditional knockout mice (7, 8).
    [Show full text]
  • Studies on the Effect of Erbb Tyrosine Kinase Inhibitors on Malignant Melanoma Growth and Survival in Vitro
    Linköping Studies in Health Sciences Thesis No. 100 Studies on the effect of ErbB tyrosine kinase inhibitors on malignant melanoma growth and survival in vitro Emelie Djerf Division of Oncology Department of Clinical and Experimental Medicine Faculty of Health Sciences, Linköping University SE-581 85 Linköping, Sweden Linköping 2009 Emelie Djerf, 2009 All rights reserved ISBN 978-91-7393-610-1 ISSN 1100-6013 Published articles have been reprinted with permission of respective copyright holder. Paper I © Lippincott Williams & Wilkins, Melanoma Research Illustrations made by the author, unless otherwise specified. II ABSTRACT Malignant melanoma has one of the fastest increasing incidences among the different types of cancer in the Western world. This raise can partly be ascribed to the change in sun habits that has taken place during the last decades, since the major external risk factor for melanoma is exposure to ultraviolet radiation. Patients with early stages of melanoma can often be cured by surgery, however for patients suffering from metastatic melanoma there are only a few treatment options available. Unfortunately malignant melanoma is often resistant to radio-, bio- and chemotherapy and treatment with the currently most frequently used agent, dacarbazine, is characterized by a very low clinical response rate. Therefore, there is an urgent need for new treatment strategies which can increase the overall survival and cause less severe side effects. The aim of this thesis was to investigate the anti-tumor effect of two different tyrosine kinase inhibitors (TKIs), gefitinib and canertinib, on two different human malignant melanoma (RaH3 and RaH5) cell lines. We investigate the effect of these two drugs on cell proliferation and survival and studied the effect of gefitinib and canertinib on ErbB1-4 receptor phosphorylation, as well as Akt, Erk1/2 and Stat3 activity.
    [Show full text]
  • Janus Kinases: Components of Multiple Signaling Pathways
    Oncogene (2000) 19, 5662 ± 5679 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Janus kinases: components of multiple signaling pathways Sushil G Rane1 and E Premkumar Reddy*,1 1Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 N. Broad Street, Philadelphia, Pennsylvania, PA 19140, USA Cytoplasmic Janus protein tyrosine kinases (JAKs) are rapidly induce tyrosine phosphorylation of the recep- crucial components of diverse signal transduction path- tors and a variety of cellular proteins suggesting that ways that govern cellular survival, proliferation, dier- these receptors transmit their signals through cellular entiation and apoptosis. Evidence to date, indicates that tyrosine kinases (Kishimoto et al., 1994). During the JAK kinase function may integrate components of past decade, new evidence has emerged to indicate that diverse signaling cascades. While it is likely that most cytokines transmit their signals via a new family activation of STAT proteins may be an important of tyrosine kinases termed JAK kinases (Ihle et al., function attributed to the JAK kinases, it is certainly 1995, 1997; Darnell, 1998; Darnell et al., 1994; not the only function performed by this key family of Schindler, 1999; Schindler and Darnell, 1995; Ward et cytoplasmic tyrosine kinases. Emerging evidence indi- al., 2000; Pellegrini and Dusanter-Fourt, 1997; Leo- cates that phosphorylation of cytokine and growth factor nard and O'Shea, 1998; Leonard and Lin, 2000; Heim, receptors may be the primary functional attribute of 1999). JAK kinases. The JAK-triggered receptor phosphoryla- Conventional protein tyrosine kinases (PTKs) pos- tion can potentially be a rate-limiting event for a sess catalytic domains ranging from 250 to 300 amino successful culmination of downstream signaling events.
    [Show full text]
  • Janus Kinases in Leukemia
    cancers Review Janus Kinases in Leukemia Juuli Raivola 1, Teemu Haikarainen 1, Bobin George Abraham 1 and Olli Silvennoinen 1,2,3,* 1 Faculty of Medicine and Health Technology, Tampere University, 33014 Tampere, Finland; juuli.raivola@tuni.fi (J.R.); teemu.haikarainen@tuni.fi (T.H.); bobin.george.abraham@tuni.fi (B.G.A.) 2 Institute of Biotechnology, Helsinki Institute of Life Science HiLIFE, University of Helsinki, 00014 Helsinki, Finland 3 Fimlab Laboratories, Fimlab, 33520 Tampere, Finland * Correspondence: olli.silvennoinen@tuni.fi Simple Summary: Janus kinase/signal transducers and activators of transcription (JAK/STAT) path- way is a crucial cell signaling pathway that drives the development, differentiation, and function of immune cells and has an important role in blood cell formation. Mutations targeting this path- way can lead to overproduction of these cell types, giving rise to various hematological diseases. This review summarizes pathogenic JAK/STAT activation mechanisms and links known mutations and translocations to different leukemia. In addition, the review discusses the current therapeutic approaches used to inhibit constitutive, cytokine-independent activation of the pathway and the prospects of developing more specific potent JAK inhibitors. Abstract: Janus kinases (JAKs) transduce signals from dozens of extracellular cytokines and function as critical regulators of cell growth, differentiation, gene expression, and immune responses. Deregu- lation of JAK/STAT signaling is a central component in several human diseases including various types of leukemia and other malignancies and autoimmune diseases. Different types of leukemia harbor genomic aberrations in all four JAKs (JAK1, JAK2, JAK3, and TYK2), most of which are Citation: Raivola, J.; Haikarainen, T.; activating somatic mutations and less frequently translocations resulting in constitutively active JAK Abraham, B.G.; Silvennoinen, O.
    [Show full text]