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Mechanisms and targeting of oncogenic MAPK signaling in myeloid malignancies

Applicant Meyer Sara Christina
Number 161145
Funding scheme Ambizione
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Experimental Cancer Research
Start/End 01.07.2016 - 30.06.2019
Approved amount 609'978.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Pathophysiology

Keywords (6)

Myeloid malignancies; Myeloproliferative neoplasms; JAK2 tyrosine kinase; MAPK signaling pathway; FLT3 tyrosine kinase; Acute myeloid leukemia

Lay Summary (German)

Lead
Mechanismen und Targeting von onkogenem MAPK Signaling bei myeloischen Leukämien
Lay summary

Das Forschungsprojekt untersucht das therapeutische Potential der kombinierten Hemmung zweier zellulärer Signalwege, die zur Entwicklung von Leukämien (Krebserkrankungen von Blut und Knochenmark) beitragen. Im Zentrum steht der sogenannte MAPK Signalweg und die Signalaktivität durch die Tyrosinkinasen JAK2 bei myeloproliferativen Neoplasien (MPN) oder FLT3 bei akuter myeloischer Leukämie (AML). Die mutierten Tyrosinkinasen JAK2 bei MPN und FLT3 bei AML sind wichtige Faktoren in der Entwicklung dieser Leukämien und es wurden Inhibitoren von JAK2 und FLT3 zur gezielten Behandlung dieser Patienten entwickelt. Eine Monotherapie mit JAK2 oder FLT3 Inhibitoren ist jedoch nur ungenugend wirksam und die Entwicklung besserer Therapieansätze ist deshalb notwendig. Unser Forschungsprojekt beinhaltet die Analyse von Leukämie-Zelllinien, präklinischen Modellen und Patientenproben. Wir beobachten, dass der MAPK Signalweg, der bei zahlreichen Krebserkrankungen eine wichtige Rolle spielt, auch bei JAK2 mutierten MPN aktiviert ist. Wir untersuchen deshalb, ob der MAPK Signalweg zu kompensatorischen Signalen in den Leukämiezellen führt, welche den Effekt der JAK2- bzw. FLT3 Inhibitoren limitieren. Wir studieren, ob die zusätzliche Hemmung des MAPK Signalwegs durch eine kombinierte Inhibition von MAPK und der Tyrosinkinasen JAK2 oder FLT3 die therapeutische Wirksamkeit verbessert. Wir untersuchen die molekularen Schritte, die zur Aktivierung des MAPK Signalwegs bei JAK2-mutierten MPN und FLT3-mutierter AML fuhren. Deren Aufklärung vermag möglicherweise weitere Vorgänge zu identifizieren, die wiederum als Angriffspunkte neuer Therapien dienen. Unsere Studien haben zum Ziel, die kombinierte Hemmung von MAPK- und Tyrosinkinase Signaling als verbesserte Therapieoption fur Leukämiepatienten voranzubringen.

Direct link to Lay Summary Last update: 17.05.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms
Meyer Sara C., Stivala Simona, Codilupi Tamara, Brkic Sime, Baerenwaldt Anne, Ghosh Nilabh, Hao-Shen Hui, Dirnhofer Stephan, Dettmer Matthias S., Simillion Cedric, Kaufmann Beat A., Chiu Sophia, Keller Matthew, Kleppe Maria, Hilpert Morgane, Buser Andreas S., Passweg Jakob R., Radimerski Thomas, Skoda Radek C., Levine Ross L. (2019), Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms, in Journal of Clinical Investigation, 129(4), 1596-1611.
Cooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity
Kunimoto H, Meydan C, Nazir A, Whitfield J, Shank K, Rapaport F, Maher R, Pronier E, Meyer SC, Garrett-Bakelman FE, Tallman M, Melnick A, Levine RL, Shih AH (2018), Cooperative Epigenetic Remodeling by TET2 Loss and NRAS Mutation Drives Myeloid Transformation and MEK Inhibitor Sensitivity, in Cancer Cell, (1), 44-59.
Mediator kinase phosphorylation of STAT1 S727 is required for neoplasms with JAK-STAT activation
Nitulescu I, Meyer SC, Wen QJ, Crispino JD, Lemieux ME, Levine RL, Pelish HE, Shair MD (2017), Mediator kinase phosphorylation of STAT1 S727 is required for neoplasms with JAK-STAT activation, in Ebiomedicine, 112.
Amotosalen/ultraviolet A pathogen inactivation technology reduces platelet activatability, induces apoptosis and accelerates clearance
Stivala Simona, Gobbato Sara, Infanti Laura, Reiner Martin F., Bonetti Nicole, Meyer Sara C., Camici Giovanni G., Lüscher Thomas F., Buser Andreas, Beer Jürg H. (2017), Amotosalen/ultraviolet A pathogen inactivation technology reduces platelet activatability, induces apoptosis and accelerates clearance, in Haematologica, 102(10), 1650-1660.
Mechanisms of Resistance to JAK2 Inhibitors in Myeloproliferative Neoplasms.
Meyer Sara C (2017), Mechanisms of Resistance to JAK2 Inhibitors in Myeloproliferative Neoplasms., in Hematology/oncology clinics of North America, 31(4), 627-642.
Anti-platelet factor 4/heparin antibody formation occurs endogenously and at unexpected high frequency in polycythemia vera.
Meyer SC, Steinmann E, Lehmann T, Muesser P, Passweg JR, Skoda RC, Tsakiris DA (2017), Anti-platelet factor 4/heparin antibody formation occurs endogenously and at unexpected high frequency in polycythemia vera., in Biomed Research International, 98768.
JAK2 exon 12 mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis
Grisouard Jean, Li Sai, Kubovcakova Lucia, Rao Tata Nageswara, Meyer Sara C., Lundberg Pontus, Hao-Shen Hui, Romanet Vincent, Murakami Masato, Radimerski Thomas, Dirnhofer Stephan, Skoda Radek C. (2016), JAK2 exon 12 mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis, in Blood, 128(6), 839-851.
Loss of Ezh2 synergizes with JAK2 -V617F in initiating myeloproliferative neoplasms and promoting myelofibrosis
Shimizu Takafumi, Kubovcakova Lucia, Nienhold Ronny, Zmajkovic Jakub, Meyer Sara C., Hao-Shen Hui, Geier Florian, Dirnhofer Stephan, Guglielmelli Paola, Vannucchi Alessandro M., Feenstra Jelena D. Milosevic, Kralovics Robert, Orkin Stuart H., Skoda Radek C. (2016), Loss of Ezh2 synergizes with JAK2 -V617F in initiating myeloproliferative neoplasms and promoting myelofibrosis, in The Journal of Experimental Medicine, 213(8), 1479-1496.

Collaboration

Group / person Country
Types of collaboration
Bioinformatics Core Facility/Department of Biomedicine, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Buser/Blutspendezentrum Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Levine/Memorial Sloan Kettering Cancer Center, New York United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dirnhofer/Institute of Pathology, University Hospital Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Skoda/Department of Biomedicine, University of Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. T. Radimerski/Novartis Biomedical Research Institutes Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Congress of the European Hematology Association 2019, Amsterdam Talk given at a conference Targeting oncogenic signaling and resistance in myeloproliferative neoplasms 14.06.2019 Amsterdam, Netherlands Meyer Sara Christina;
MDS/MPN Symposium 2019, University Hospital Basel Talk given at a conference Vortrag 22.05.2019 Basel, Switzerland Meyer Sara Christina;
MDS/MPN Symposium 2018, University Hospital Basel Talk given at a conference Case Presentation MPN: Recurrent splenomegaly on ruxolitinib in MPN - does resistance to ruxolitinib exist? 23.05.2018 Basel, Switzerland Meyer Sara Christina;
Annual Meeting, American Society of Hematology 2017 Talk given at a conference Targeting Cell Non-Autonomous MAPK Activation As a Novel Therapeutic Strategy in Myeloproliferative Neoplasms 08.12.2017 Atlanta, United States of America Meyer Sara Christina;
MDS/MPN Symposium 2017, University Hospital Basel Talk given at a conference Next-generation JAK2 inhibitors in myeloproliferative neoplasms 10.05.2017 Basel, Switzerland Meyer Sara Christina;


Awards

Title Year
European School of Hematology ESH / MPN Research Foundation Scholarship 2018

Associated projects

Number Title Start Funding scheme
181357 Characterization of resistance to tyrosine kinase inhibition as a basis for novel therapeutic approaches in myeloid malignancies 01.07.2019 Eccellenza

Abstract

Mechanisms and targeting of oncogenic MAPK signaling in myeloid malignanciesLeukemia cells are driven by dysregulated oncogenic signaling. Somatic mutations in tyrosine kinases are a frequent cause for constitutive activation of cellular signaling. The elucidation of signaling mechanisms in myeloid leukemias enables the identification of therapeutic targets. This Ambizione/SCORE proposal addresses the role of oncogenic MAPK signaling in tyrosine kinase mutant myeloid malignancies including myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML).MPN show excessive, clonal proliferation of mature myeloid cells. They result in acute myeloid leukemia (AML) or bone marrow failure. Most MPN patients carry somatic mutations in the JAK2 pathway. JAK2 is an intracellular tyrosine kinase associated with hematopoietic cytokine receptors. JAK2 dependent signaling is constitutively activated including STAT, phosphoinositide-3 kinase (PI3K) and mitogen activated protein kinase (MAPK) signaling. This has led to the development of JAK2 inhibitors. Despite certain benefits, they fail to induce molecular remission and elicit resistance. AML shows clonal accumulation of leukemic blasts, immature myeloid progenitor cells unable to differentiate. The most frequent somatic mutations affect FLT3, a receptor tyrosine kinase in hematopoietic progenitors. MAPK, PI3K and STAT5 signaling are constitutively activated. FLT3 inhibitors have been developed but show limited response rates. A better understanding of oncogenic signaling by mutant tyrosine kinases as FLT3 and JAK2 is required to enable more effective therapeutic strategies.Own research & rationale: We developed a new mode to inhibit JAK2 which is highly effective in MPN. This type II JAK inhibition reduces mutant allele burden suggesting curative potential, and abrogates resistance to conventional (type I) inhibitors. However, we observe that MAPK signaling in murine MPN remains activated in the setting of type I or II JAK2 inhibition. This suggests additional, JAK2 independent MAPK activation which bypasses tyrosine kinase inhibition. Similar observations have been made in FLT3 mutant AML. This highlights the role of MAPK signaling in myeloid malignancies including MPN and AML.Aims: 1. We will evaluate the extent of MAPK activation in tyrosine kinase mutant myeloid malignancies including MPN and AML in murine models and patient samples.2. We want to elucidate the mechanisms of MAPK activation in the setting of tyrosine kinase inhibition3. We aim to validate the therapeutic potential of dual tyrosine kinase / MAPK inhibitionHypotheses: - MAPK signaling in kinase mutant MPN/AML is activated in vitro and in vivo through mutant kinase signaling. In vivo, additional tyrosine kinase independent MAPK activation, mediated by cell non autonomous receptor signaling, provides a bypass for tyrosine kinase inhibition.- Dual MAPK and tyrosine kinase inhibition is superior to kinase inhibitor monotherapy in leukemia models and patient samples.Significance: The molecular dissection of oncogenic MAPK signaling in kinase mutant myeloid malignancies will promote targeted therapeutic approaches of dual pathway inhibition in MPN and AML.
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