Exploitation of the fibrinolytic system by B-cell acute lymphoblastic leukemia and its therapeutic targeting

Valentina R. Minciacchi, Jimena Bravo, Christina Karantanou, Raquel S. Pereira, Costanza Zanetti, Rahul Kumar, Nathalie Thomasberger, Pablo Llavona, Theresa Krack, Katrin Bankov, Melanie Meister, Sylvia Hartmann, Véronique Maguer-Satta, Sylvain Lefort, Mateusz Putyrski, Andreas Ernst, Brian J. P. Huntly, Eshwar Meduri, Wolfram Ruf and Daniela S. Krause ()
Additional contact information
Valentina R. Minciacchi: Johannes Gutenberg University Medical Center
Jimena Bravo: Johannes Gutenberg University Medical Center
Christina Karantanou: Department of Vascular Dysfunction - Medical Faculty Mannheim of Heidelberg University
Raquel S. Pereira: Goethe-University Frankfurt
Costanza Zanetti: Helmholtz Institute for Translational Oncology Mainz
Rahul Kumar: Johannes Gutenberg University Medical Center
Nathalie Thomasberger: BioNTech SE
Pablo Llavona: The Institute of Molecular Biology
Theresa Krack: Johannes Gutenberg University Medical Center
Katrin Bankov: Charité-Universitätsmedizin
Melanie Meister: AbbVie
Sylvia Hartmann: Goethe University
Véronique Maguer-Satta: Centre Léon Bérard
Sylvain Lefort: Centre Léon Bérard
Mateusz Putyrski: Project Group Translational Medicine & Pharmacology TMP
Andreas Ernst: Goethe-University Frankfurt
Brian J. P. Huntly: University of Cambridge
Eshwar Meduri: University of Cambridge
Wolfram Ruf: Johannes Gutenberg University Medical Center
Daniela S. Krause: Johannes Gutenberg University Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract 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+ 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.

Date: 2024
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DOI: 10.1038/s41467-024-54361-4

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