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Role and molecular targets of the transcription factor EVI1 in lymphoblastic leukemia and blood stem cell development

English title Role and molecular targets of the transcription factor EVI1 in lymphoblastic leukemia and blood stem cell development
Applicant Lengerke Claudia
Number 149735
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Experimental Cancer Research
Start/End 01.12.2013 - 28.02.2017
Approved amount 347'000.00
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All Disciplines (3)

Discipline
Experimental Cancer Research
Embryology, Developmental Biology
Pathophysiology

Keywords (7)

zebrafish; EVI1; hematopoietic stem cells; hematopoiesis; xenotransplantation; developmental hematopoiesis; acute lymphoblastic leukemia

Lay Summary (German)

Lead
Erkenntnisse aus der Entwicklungsbiologie liefern Einblicke in die Entstehung von Tumorerkrankungen, da genetische Mechanismen aus der Embryonalentwicklung während der Krebsausbildung reaktiviert werden können. So reguliert der Transkriptionsfaktor EVI1 die embryonale Blutzellentwicklung und auch die Aggressivität bestimmter Leukämieformen. Unser Ziel ist die Untersuchung der Mechanismen durch welche EVI1 diese Prozesse steuert, um dadurch die Behandlung EVI1-positiver Leukämien zu verbessern.
Lay summary

Unser übergeordnetes Ziel ist die Erforschung der Bedeutung embryonaler Faktoren in der Entstehung von Krebserkrankungen. Der Transkriptionsfaktor EVI1 wird während der Embryonalentwicklung in verschiedenen Geweben und im Erwachsenenalter in verschiedenen Tumorarten nachgewiesen. Unsere Arbeitsgruppe konnte EVI1 in akuten lymphoblastischen Leukämien (ALL) nachweisen und zeigen, dass EVI1 den Zelltod nach Chemotherapie vermindert. Im vorliegenden Projekt soll untersucht werden, ob EVI1 ebenfalls durch Beeinflussung der Migration und selektiven Erhalt der „Leukämiestammzellen“ die Aggressivität der Erkrankung fördert und ob Nachweis von EVI1 bei Diagnosestellung einen ungünstigen klinischen Verlauf voraussagen kann. Es sollen die molekularen Mechanismen erforscht werden, die EVI1 während der Krebsentwicklung anschalten oder die von EVI1 benutzt werden. Die Bedeutung von EVI1 wird parallel während der embryonalen Blutbildung im Zebrafisch untersucht.

Unsere Ergebnisse könnten die Behandlung und Prognoseeinschätzung von Patienten mit EVI1-positiver ALL verbessern. Des Weiteren liefern sie wertvolle Erkenntnisse für das Verständnis anderer EVI1-positiver Tumorarten.

Direct link to Lay Summary Last update: 16.10.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Stem Cell Mobilization Methods and Protocols
Konantz Martina, Müller Joëlle S., Lengerke Claudia (2019), Stem Cell Mobilization Methods and Protocols, Springer New York, New York, NY.
Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond–like features
Carapito Raphael, Konantz Martina, Paillard Catherine, Miao Zhichao, Pichot Angélique, Leduc Magalie S., Yang Yaping, Bergstrom Katie L., Mahoney Donald H., Shardy Deborah L., Alsaleh Ghada, Naegely Lydie, Kolmer Aline, Paul Nicodème, Hanauer Antoine, Rolli Véronique, Müller Joëlle S., Alghisi Elisa, Sauteur Loïc, Macquin Cécile, Morlon Aurore, Sancho Consuelo Sebastia, Amati-Bonneau Patrizia, Procaccio Vincent, et al. (2017), Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond–like features, in Journal of Clinical Investigation, 127(11), 4090-4103.
Long-term observation reveals high-frequency engraftment of human acute myeloid leukemia in immunodeficient mice
Paczulla Anna M., Dirnhofer Stephan, Konantz Martina, Medinger Michael, Salih Helmut R., Rothfelder Kathrin, Tsakiris Dimitrios A., Passweg Jakob R., Lundberg Pontus, Lengerke Claudia (2017), Long-term observation reveals high-frequency engraftment of human acute myeloid leukemia in immunodeficient mice, in Haematologica, 102(5), 854-864.
Prominent Oncogenic Roles of EVI1 in Breast Carcinoma
Wang Hui, Schaefer Thorsten, Konantz Martina, Braun Martin, Varga Zsuzsanna, Paczulla Anna M., Reich Selina, Jacob Francis, Perner Sven, Moch Holger, Fehm Tanja N., Kanz Lothar, Schulze-Osthoff Klaus, Lengerke Claudia (2017), Prominent Oncogenic Roles of EVI1 in Breast Carcinoma, in Cancer Research, 77(8), 2148-2160.
Long-term observation reveals high-frequency engraftment of human acute myeloid leukemia in immunodeficient mice.
Paczulla Anna M, Dirnhofer Stephan, Konantz Martina, Medinger Michael, Salih Helmut R, Rothfelder Kathrin, Tsakiris Dimitrios A, Passweg Jakob R, Lundberg Pontus, Lengerke Claudia (2017), Long-term observation reveals high-frequency engraftment of human acute myeloid leukemia in immunodeficient mice., in Haematologica, 102(5), 854-864.
Prominent Oncogenic Roles of EVI1 in Breast Carcinoma.
Wang Hui, Schaefer Thorsten, Konantz Martina, Braun Martin, Varga Zsuzsanna, Paczulla Anna M, Reich Selina, Jacob Francis, Perner Sven, Moch Holger, Fehm Tanja N, Kanz Lothar, Schulze-Osthoff Klaus, Lengerke Claudia (2017), Prominent Oncogenic Roles of EVI1 in Breast Carcinoma., in Cancer research, 77(8), 2148-2160.
Evi1 regulates Notch activation to induce zebrafish hematopoietic stem cell emergence
Konantz Martina, Alghisi Elisa, Müller Joëlle S, Lenard Anna, Esain Virginie, Carroll Kelli J, Kanz Lothar, North Trista E, Lengerke Claudia (2016), Evi1 regulates Notch activation to induce zebrafish hematopoietic stem cell emergence, in The EMBO Journal, 35(21), 2315-2331.
Endothelial-to-hematopoietic transition: Notch-ing vessels into bloodEndothelial-to-hematopoietic transition
Kanz Dirk, Konantz Martina, Alghisi Elisa, North Trista E., Lengerke Claudia (2016), Endothelial-to-hematopoietic transition: Notch-ing vessels into bloodEndothelial-to-hematopoietic transition, in Annals of the New York Academy of Sciences, 1370(1), 97-108.
Endothelial-to-hematopoietic transition: Notch-ing vessels into blood.
Kanz Dirk, Konantz Martina, Alghisi Elisa, North Trista E, Lengerke Claudia (2016), Endothelial-to-hematopoietic transition: Notch-ing vessels into blood., in Annals of the New York Academy of Sciences, 1370(1), 97-108.
Evi1 regulates Notch activation to induce zebrafish hematopoietic stem cell emergence.
Konantz Martina, Alghisi Elisa, Müller Joëlle S, Lenard Anna, Esain Virginie, Carroll Kelli J, Kanz Lothar, North Trista E, Lengerke Claudia (2016), Evi1 regulates Notch activation to induce zebrafish hematopoietic stem cell emergence., in The EMBO journal, 35(21), 2315-2331.

Collaboration

Group / person Country
Types of collaboration
Holger Moch, Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Stephan Dirnhofer, University of Basel and University Hospital Basel, Department of Pathology Switzerland (Europe)
- Publication
- Research Infrastructure
Prof. Dr. Klaus Schulze-Osthoff, University of Tübingen, Department of Biochemistry Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dimitrios A. Tsakiris, University of Basel and University Hospital Basel, Diagnostic Hematology Switzerland (Europe)
- Publication
- Research Infrastructure
Prof. Leonard Zon, Children´s Hospital Boston, Harvard Medical School United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Dr. Sven Perner, University of Bonn, Department of Pathology Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Timm Schroeder, Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
PD Dr. Leticia Quintanilla-Martinez, University of Tübingen, Department of Pathology Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. Trista North, Beth Israel Deaconess Medical Center, Department of Experimental Pathology United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Pontus Lundberg, Diagnostic Hematology, University Hospital Basel, Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. George Q. Daley, Children´s Hospital Boston, Harvard Medical School United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Ivan Martin, Department of Biomedicine, University Hospital Basel, Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Dr. Jakob Passweg, Universitätsspital Basel, Hämatologie Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Tanja N. Fehm, Department of Gynecology and Obstetrics, University Hospital Duesseldorf Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Zsuzsanna Varga, Pathology and Molecular Pathology, University Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Christian Mosimann, University of Zürich, Institute of Molecular Life Sciences Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Radek Skoda, Department of Biomedicine, University Hospital Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Helmut R. Salih, University Hospital Tübingen, Medical Clinic II Germany (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
9th ZDM (Zebrafish Disease Models) Conference Talk given at a conference Evi1 regulates Notch activation to induce zebrafish hematopoietic stem cell emergence 04.10.2016 Singapur, Singapore Lengerke Claudia; Alghisi Elisa;
Annual Meeting of the DGHO (Deutsche Gesellschaft für Hämatologie und Onkologie) Talk given at a conference Zebrafish xenografts as a tool for in vivo studies on human leukemia 10.10.2015 Hamburg, Germany Paczulla Anna; Lengerke Claudia;
Annual Meeting of the DGHO (Deutsche Gesellschaft für Hämatologie und Onkologie) Talk given at a conference The zebrafish homologue of the murine Evi1 gene critically regulates HSC development via the NOTCH pathway 09.10.2015 Basel, Switzerland Lengerke Claudia; Alghisi Elisa;
44th Annual Scientific Meeting of the International-Society-for-Experimental-Hematology (ISEH) Poster The zebrafish homologue of the murine evi1 gene critically regulates HSC development 17.09.2015 Kyoto, Japan Alghisi Elisa; Lengerke Claudia;
SSH (Swiss Society of Hematology) Annual Meeting Talk given at a conference The zebrafish homologue of the murine Evi1 gene critically regulates HSC development 20.05.2015 Basel, Switzerland Alghisi Elisa; Lengerke Claudia;
Hematopoietic Stem Cells IX International Conference and Workshop Talk given at a conference Endothelial-to-hematopoietic transition: Notch-ing vessels into blood 20.04.2015 Tübingen, Germany Lengerke Claudia;
8th Annual Swiss Zebrafish Meeting Talk given at a conference The zebrafish homologue of the evi1 gene critically regulates hematopoietic stem cell development 10.04.2015 Fribourg, Switzerland Lengerke Claudia;
56th annual meeting of the American Society of Hematology (ASH) Poster Multiple Roles for the Zebrafish Homologue of the Murine Evi1 Gene during Primitive Myelopoiesis and HSC Development 06.12.2014 San Fransisco, United States of America Lengerke Claudia;
SSH (Swiss Society of Hematology) Annual Meeting Talk given at a conference EVI1 regulates apoptosis resistance of human ALL cells by activation of BCL-x 14.05.2014 Geneva, Switzerland Lengerke Claudia;
SSH (Swiss Society of Hematology) Annual Meeting Talk given at a conference The transcription factor evi1 critically regulates developmental haematopoiesis 14.05.2014 Geneva, Switzerland Lengerke Claudia;
7th Annual Swiss Zebrafish Meeting Talk given at a conference Zebrafish xenografts as a model for in vivo studies on human cancer cells 24.04.2014 Geneva, Switzerland Paczulla Anna; Lengerke Claudia;


Self-organised

Title Date Place

Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Career path translational scientist in academic medicine Workshop 25.03.2017 Thun (Meeting of the Medical Women Switzerland), Switzerland Lengerke Claudia;
Annual summer school in transplantation immunology Talk 30.06.2016 University of Strassbourg, France Lengerke Claudia;
Workshop "Pesonalized Medicine in Oncology" (Summer School) Workshop 06.09.2014 Nice, France Lengerke Claudia;


Awards

Title Year
Award of the Swiss Society of Hematology for the best work in Experimental Hematology, Lausanne, Switzerland (2017) 2017
Best Abstract Award, Annual Meeting of the DGHO (Deutsche Gesellschaft für Hämatologie und Onkologie), Basel, Switzerland 2015
Abstract Achievement award of the American Society of Hematology (ASH), San Fransisco, USA 2014
Award of the Swiss Society of Hematology for the best work in Experimental Hematology, Geneva, Switzerland 2014

Abstract

SUMMARY OF THE RESEARCH PLANTranscription factors which direct blood cell development during embryogenesis (e.g. SCL, MLL, AML1/RUNX1) can reactivate expression in adult hematopoietic cells and induce malignant transformation (e.g. leukemia). We have previously identified the BMP-Wnt-CDX-HOX signaling pathway as an essential regulator of developmental hematopoiesis and have demonstrated involvement of CDX genes in the pathogenesis of human myeloid and lymphoid leukemia. To investigate the molecular targets of CDX2, we performed gene expression arrays on acute lymphoblastic leukemia (ALL) cells after CDX2 inhibition and identified the transcription factor EVI1 as a potential downstream gene. Consistently, CDX-mutant zebrafish embryo displayed reduced expression of the zebrafish homologue evi1.Originally identified as a retroviral insertion site in myeloid neoplasia, EVI1 has been intensively studied in mye-loid leukemia. Recently, we showed that EVI1 is also expressed in cell lines and primary samples from patients with lymphatic malignancies. In a pilot cohort of 31 patients with pediatric ALL, high EVI1 transcripts were de-tectable in ca. 10% of patients and associated with adverse clinical outcome (p=0.02). Knockdown of EVI1 in human ALL cells enhanced apoptosis sensitivity, suppressed in vivo leukemogenesis and enhanced overall sur-vival of xenotransplanted NSG mice (p<0.003). EVI1 also critically regulates embryonic blood development influencing primitive myelopoiesis (but not erythropoiesis) as well as stem cell formation, but the underlying molecular mechanisms are poorly understood. The current research proposal aims to further characterize the roles of EVI1 and the underlying molecular mechanisms in ALL and blood stem cell development. Following aims shall be addressed:1.To analyze functional roles of EVI1 in ALL (e.g. homing and migration, in vivo modulation of response to TRAIL-agonists, regulation of leukemia stem cells, behavior in zebrafish xenografts) and blood stem cell development (specification versus proliferation/survival)2.To identify EVI1 molecular targets and upstream regulatory mechanisms 3.To further analyze the prognostic significance of EVI1 expression in ALLSignificance: Elucidation of EVI1 driven functions and molecular mechanisms may provide rationales for novel therapies and targets for specific intervention in ALL. The obtained results may apply to several other tumor entities where EVI1 is a well-recognized oncogene. Analysis of EVI1 expression may contribute to the identifica-tion of patients with high-risk ALL.
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