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Modeling for targeting of acute myeloid leukemia driven by epigenetic mechanisms

English title Modeling for targeting of acute myeloid leukemia driven by epigenetic mechanisms
Applicant Schwaller Jürg
Number 173224
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 01.09.2017 - 28.02.2023
Approved amount 948'622.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Pathophysiology

Keywords (4)

Mouse models; Acute myeloid leukemia; Cancer; Epigenetics

Lay Summary (German)

Lead
Die sogenannte akute myeloische Leukämie (AML) ist eine der häufigsten Blutkrebsformen welche trotz modernster Medizin in den meisten Fällen nicht geheilt werden kann. Unsere Forschung versucht die molekularen Grundlagen dieser Krankheit zu verstehen, um neue Strategien zur gezielten Therapie zu entwickeln.
Lay summary

Inhalt und Ziel des Forschungsprojektes

Forschung der letzten 30 Jahre konnte zeigen, dass die akute myeloische Leukämie (AML) die Folge einer relativ geringen Zahl funktionell zusammenarbeitender genetischen Mutationen in den blutbildenden Zellen des Knochenmarks ist. In früheren Studien konnten wir zeigen, dass die Zelle, in welcher sich diese Mutationen zuerst ausbilden die Biologie und die Klinik der Krankheit bestimmen. Wir fanden auch Hinweise dafür, dass die Ursprungszellen auch das Zusammenspiel leukämischer Zellen mit anderen Knochenmarkszellen (dem sogenannten „Stroma“) kritisch beeinflussen.

Im aktuellen Projekt entwickeln wir ein neues Modell welches es uns erlaubt die molekularen Vorgänge von der normalen Blutstammzelle bis zur symptomatischen AML zu verfolgen. Wir versuchen auch zu verstehen warum nicht aus allen Blutstammzellen eine AML entstehen kann. Im weitern versuchen wir Gene zu identifizieren welche die Aggressivität leukämischer Zellen bestimmen. Schlussendlich wollen wir kritische Interaktionen leukämischer Zellen mit dem Stroma entschlüsseln.

Unsere Experimente kombinieren verschiedene Zell-Modelle von Mensch und Tier (Maus) mit modernsten molekular-genetischen Methoden. Mit diesen Experimenten hoffen wir die Grundlagen neuer Therapien und eventuell auch der Prävention von AML, und anderen Formen von Blutkrebs zu finden.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Dies ist ein Grundlagenforschungsprojekt mit einer starken translatorischen Komponente. Um die genetisch komplexen und heterogenen Blutkrebsformen zu studieren, ist es wichtig nicht nur die molekularen Grundlagen zu beschreiben, sondern auch neue Modelle zu etablieren, welche es erlauben deren Funktion in einem lebenden Organismus zu verstehen. Erst dadurch wird es möglich Erkenntnisse zur gezielten personalisierten Therapie zu erarbeiten.

Direct link to Lay Summary Last update: 31.07.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Learning from mouse models of MLL fusion gene-driven acute leukemia
Schwaller Juerg (2020), Learning from mouse models of MLL fusion gene-driven acute leukemia, in Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 1863(8), 194550-194550.
Human erythroleukemia genetics and transcriptomes identify master transcription factors as functional disease drivers
Fagnan Alexandre, Bagger Frederik Otzen, Piqué-Borràs Maria-Riera, Ignacimouttou Cathy, Caulier Alexis, Lopez Cécile, Robert Elie, Uzan Benjamin, Gelsi-Boyer Véronique, Aid Zakia, Thirant Cécile, Moll Ute, Tauchmann Samantha, Kurtovic-Kozaric Amina, Maciejewski Jaroslaw P, Dierks Christine, Spinelli Orietta, Salmoiraghi Silvia, Pabst Thomas, Shimoda Kazuya, Deleuze Virginie, Lapillonne Helene, Sweeney Connor, Mansat-De Mas Veronique, et al. (2020), Human erythroleukemia genetics and transcriptomes identify master transcription factors as functional disease drivers, in Blood.
Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene–Driven Myeloid Leukemia
Lopez Cécile K., Noguera Esteve, Stavropoulou Vaia, Robert Elie, Aid Zakia, Ballerini Paola, Bilhou-Nabera Chrystèle, Lapillonne Hélène, Boudia Fabien, Thirant Cécile, Fagnan Alexandre, Arcangeli Marie-Laure, Kinston Sarah J., Diop M'Boyba, Job Bastien, Lecluse Yann, Brunet Erika, Babin Loélia, Villeval Jean Luc, Delabesse Eric, Peters Antoine H.F.M., Vainchenker William, Gaudry Muriel, Masetti Riccardo, et al. (2019), Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene–Driven Myeloid Leukemia, in Cancer Discovery, 9(12), 1736-1753.
Pediatric Acute Myeloid Leukemia (AML): From Genes to Models Toward Targeted Therapeutic Intervention
Mercher Thomas, Schwaller Juerg (2019), Pediatric Acute Myeloid Leukemia (AML): From Genes to Models Toward Targeted Therapeutic Intervention, in Frontiers in Pediatrics, 7, 466.
Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion
Paczulla Anna M., Rothfelder Kathrin, Raffel Simon, Konantz Martina, Steinbacher Julia, Wang Hui, Tandler Claudia, Mbarga Marcelle, Schaefer Thorsten, Falcone Mattia, Nievergall Eva, Dörfel Daniela, Hanns Pauline, Passweg Jakob R., Lutz Christoph, Schwaller Juerg, Zeiser Robert, Blazar Bruce R., Caligiuri Michael A., Dirnhofer Stephan, Lundberg Pontus, Kanz Lothar, Quintanilla-Martinez Leticia, Steinle Alexander, et al. (2019), Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion, in Nature, 572(7768), 254-259.
The Impact of the Cellular Origin in Acute Myeloid LeukemiaLearning From Mouse Models
Fisher James Neil, Kalleda Natarajaswamy, Stavropoulou Vaia, Schwaller Juerg (2019), The Impact of the Cellular Origin in Acute Myeloid LeukemiaLearning From Mouse Models, in HemaSphere, 3(1), e152-e152.
Murine Models of Acute Myeloid Leukaemia
Almosailleakh Marwa, Schwaller Juerg (2019), Murine Models of Acute Myeloid Leukaemia, in International Journal of Molecular Sciences, 20(2), 453-453.
Novel insights into the role of aberrantly expressed MNX1 (HLXB9) in infant acute myeloid leukemia
Schwaller Juerg (2018), Novel insights into the role of aberrantly expressed MNX1 (HLXB9) in infant acute myeloid leukemia, in Haematologica, 104(1), 1-3.
A Novel Inducible Mouse Model of MLL-ENL-driven Mixed-lineage Acute Leukemia
Stavropoulou Vaia, Almosailleakh Marwa, Royo Hélène, Spetz Jean-François, Juge Sabine, Brault Laurent, Kopp Patrick, Iacovino Michelina, Kyba Michael, Tzankov Alexandar, Stadler Michael B., Cazzaniga Gianni, Peters Antoine H.F.M., Schwaller Juerg (2018), A Novel Inducible Mouse Model of MLL-ENL-driven Mixed-lineage Acute Leukemia, in HemaSphere, 2(4), 1-1.
ZEB Proteins in LeukemiaFriends, Foes, or Friendly Foes?
Soen Bieke, Vandamme Niels, Berx Geert, Schwaller Jürg, Van Vlierberghe Pieter, Goossens Steven (2018), ZEB Proteins in LeukemiaFriends, Foes, or Friendly Foes?, in HemaSphere, 2(3), e43-e43.
LEDGF/p75 Is Dispensable for Hematopoiesis but Essential for MLL-rearranged Leukemogenesis
El AshkarSara (2018), LEDGF/p75 Is Dispensable for Hematopoiesis but Essential for MLL-rearranged Leukemogenesis, in Blood, 131(1), 95-107.
Transforming activities of the NUP98-KMT2A fusion gene associated with myelodysplasia and acute myeloid leukemia
FisherJames Neil, Transforming activities of the NUP98-KMT2A fusion gene associated with myelodysplasia and acute myeloid leukemia, in Haematologica.

Associated projects

Number Title Start Funding scheme
149714 Modeling and molecular targeting of MLL acute leukemia 01.10.2013 Project funding (Div. I-III)
130661 Functional dissection of molecular mechanisms and cellular targets of MLL Leukemia 01.04.2010 Project funding (Div. I-III)
149714 Modeling and molecular targeting of MLL acute leukemia 01.10.2013 Project funding (Div. I-III)

Abstract

1. SUMMARY Background: Acute myeloid leukemia (AML) is the product of a limited number of cooperating mutations such as fusions involving the mixed lineage leukemia (MLL) gene. We recently demonstrated that the cell-of-origin is a critical nominator for the biology and the clinical outcome of the disease. Expression of the MLL-AF9 fusion in long-term repopulating hematopoietic stem cells (LT-HSC) resulted in an unusually invasive AML associated with an epithelial-mesenchymal transition (EMT)-like gene signature linked to poor outcome of AML patients. We also obtained proof of concept that the bone marrow (BM) microenvironment supports MLL-AF9-driven AML by regulating oxidative stress. To further characterize the role of the cellular origin and the microenvironment in AML we aim to: 1) Explore the origin-related epigenetic dynamics in AML: Increasing evidence suggests that epigenetic mechanisms might drive AML progression. To dissect cooperating epigenetic mechanisms during disease progression we will establish a novel transgenic mouse model that allows tracking and enrichment of cells expressing the driving MLL-AF9 fusion to compare origin-related dynamic changes of chromatin conformation, gene expression and DNA methylation at different stages of the disease. 2) Characterize the cellular origin of LT-HSC-derived AML: Aggressive LT-HSC-derived MLL-AF9 driven AML is associated with high expression levels of the transcription factors Evi1 and Erg. Likewise, EVI1 and ERG expression characterized AML patients with poor outcome. To better understand the cellular origin of this particularly invasive AML, we aim to explore whether expression of EVI1/ERG or a dynamic cellular identity determines the susceptibility of LT-HSC for transformation by a leukemogenic fusion gene.3) Characterize the putative drivers of invasive LT-HSC-derived AML: Aggressive LT-HSC-derived MLL-AF9 AML is characterized by expression of genes related to invasion and/or EMT. Several genes of this signature characterized the outcome of AML patients not limited to MLL rearrangements. Therefore systematic characterization of their role for development and maintenance of AML may reveal novel drivers and future therapeutic targets.4) Dissect the critical crosstalk between AML and the BM microenvironment: The BM microenvironments of AML patients or diseased iMLL-AF9 transgenic mice contain an increased number of nestin-expressing mesenchymal stroma cells (Nes+BM-MSC). Preliminary observations suggest that Nes+BM-MSC protect AML blasts from oxidative stress. We will use the iMLL-AF9 mouse model to identify regulators of oxidative stress critical for AML induction and maintenance. Significance: Despite treatment with chemotherapy and stem cell transplants most AML patients relapse and die from their disease urging the need for novel therapeutic strategies. We have previously provided evidence that the cellular origin is a major indicator for disease outcome. The proposed research will identify and validate origin-related targets and dissect cooperating epigenetic mechanisms to open the avenue for therapeutic interference of disease progression or chemoprevention. Furthermore, dissection of the crosstalk between the leukemic blasts and the protecting BM niche will provide proof of concept for combined therapeutic targeting of tumor cells and the microenvironment.
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