Exploitation of the fibrinolytic system by B-cell acute lymphoblastic leukemia and its therapeutic targeting
Fibrinolysis influences the mobilization of hematopoietic stem cells from their bone marrow microenvironment (BMM). Here we show that activation of plasmin, a key fibrinolytic agent, by annexin A2 (ANXA2) distinctly impacts progression of BCR-ABL1<sup>+</sup> B-cell acute lymphoblastic leukemia (B-ALL) via modulation of the extracellular matrix (ECM) in the BMM. The dense ECM in a BMM with decreased plasmin activity entraps insulin-like growth factor (IGF) 1 and reduces mTORC2-dependent signaling and proliferation of B-ALL cells. Conversely, B-ALL conditions the BMM to induce hepatic generation of plasminogen, the plasmin precursor. Treatment with ε-aminocaproic acid (EACA), which inhibits plasmin activation, reduces tumor burden and prolongs survival, including in xenogeneic models via increased fibronectin in the BMM. Human data confirm that IGF1 and fibronectin staining in trephine biopsies are correlated. Our studies suggest that fibrinolysis-mediated ECM remodeling and subsequent growth factor release influence B-ALL progression and inhibition of this process by EACA may be beneficial as adjunct therapy.
Authors
- Wolfram Ruf (ORCID: https://orcid.org/0000-0002-6064-2166)
- Daniela S. Krause (ORCID: https://orcid.org/0000-0003-3603-1119)
- Melanie Meister (ORCID: https://orcid.org/0000-0003-0853-6750)
- Christina Karantanou (ORCID: https://orcid.org/0000-0002-2161-914X)
- Sylvain Lefort (ORCID: https://orcid.org/0000-0001-7320-4256)
- Mateusz Putyrski
- Brian J.P. Huntly (ORCID: https://orcid.org/0000-0003-0312-161X)
- Véronique Maguer‐Satta (ORCID: https://orcid.org/0000-0002-1556-068X)
- Raquel Pereira (ORCID: https://orcid.org/0000-0002-9863-6538)
- Sylvia Hartmann (ORCID: https://orcid.org/0000-0003-3424-1091)
- Costanza Zanetti (ORCID: https://orcid.org/0000-0001-9384-1543)
- Eshwar Meduri (ORCID: https://orcid.org/0000-0002-3821-312X)
- Valentina R. Minciacchi (ORCID: https://orcid.org/0000-0002-9296-9403)
- Katrin Bankov (ORCID: https://orcid.org/0009-0005-4033-4966)
- Rahul Kumar (ORCID: https://orcid.org/0000-0002-0934-0859)
- Pablo Llavona (ORCID: https://orcid.org/0000-0003-2520-1055)
- Jimena Bravo (ORCID: https://orcid.org/0000-0002-3237-1020)
- Theresa Krack
- Nathalie Thomasberger
- Andreas Ernst (ORCID: https://orcid.org/0000-0001-5122-5005)
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Goethe University Frankfurt (DE)
- Centre National de la Recherche Scientifique (FR)
- Scripps Institution of Oceanography (US)
- Inserm (FR)
- German Cancer Research Center (DE)
- Johannes Gutenberg University Mainz (DE)
- Heidelberg University (DE)
- University of Cambridge (GB)
- University Hospital Heidelberg (DE)
- Institute for Transfusion Medicine (US)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Centre Léon Bérard (FR)
- Helmholtz Institute Mainz (DE)
- Centre de Recherche en Cancérologie de Lyon (FR)
- AbbVie (Germany) (DE)
- Fraunhofer Institute for Molecular Biology and Applied Ecology (DE)
- BioNTech (Germany) (DE)
- Scripps (United States) (US)
- University Medical Centre Mannheim (DE)
- Institute of Molecular Biology (DE)
- Helmholtz Institute for Translational Oncology Mainz
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-20
- DOI
- https://doi.org/10.1038/s41467-024-54361-4
- Citations
- 5
- Primary Topic
- S100 Proteins and Annexins
- Type
- article
- Field-Weighted Citation Impact
- 1.17
Funders
- Deutsches Krebsforschungszentrum
- Deutsche Forschungsgemeinschaft
- Else Kröner-Fresenius-Stiftung
- Medical Research Council
- Universitätsmedizin der Johannes Gutenberg-Universität Mainz