Journal Article

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

Kumar, Rahul, Karantanou, Christina, Krause, Daniela S., Ernst, Andreas, Bravo, Jimena, Putyrski, Mateusz, Huntly, Brian J. P., Thomasberger, Nathalie, Krack, Theresa, Minciacchi, Valentina R., Hartmann, Sylvia, Zanetti, Costanza, Lefort, Sylvain, Meduri, Eshwar, Bankov, Katrin, Maguer-Satta, Véronique, Ruf, Wolfram, Meister, Melanie, Pereira, Raquel S., Llavona, Pablo

2024

Overview

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. The fibrinolytic system promotes the progression of solid tumors. Here, the authors show that the fibrinolytic agent plasmin supports B-cell acute lymphoblastic leukemia (B-ALL) progression via remodeling of the extracellular matrix, and the inhibition of plasmin activation with ε-aminocaproic acid prolongs survival in B-ALL mouse models.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/2 / 13/21 / 13/31 / 13/51 / 13/95 / 14 / 14/19 / 38/61 / 38/91 / 49 / 631/67/1990/283 / 64 / 64/60 / 692/308/575 / 692/4028/67/1990/283/2125 / Acute lymphoblastic leukemia / Animal models / Animals / Annexin A2 - metabolism / BCR-ABL protein / Beta cells / Biopsy / Bone marrow / Bone Marrow - metabolism / Bone Marrow - pathology / Cancer / Cell activation / Cell Line, Tumor / Cell proliferation / Cell Proliferation - drug effects / Extracellular matrix / Extracellular Matrix - metabolism / Female / Fibrin / Fibrinolysin - metabolism / Fibrinolysis / Fibrinolysis - drug effects / Fibronectin / Fibronectins - metabolism / Growth factors / Hematopoietic stem cells / Humanities and Social Sciences / Humans / Insulin-like growth factor I / Insulin-Like Growth Factor I - metabolism / Insulin-like growth factors / Leukemia / Life Sciences / Lymphatic leukemia / Male / Mice / Mice, SCID / Microenvironments / multidisciplinary / Pharmacology / Plasmin / Plasminogen - metabolism / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism / Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology / Science / Science (multidisciplinary) / Signal Transduction - drug effects / Solid tumors / Stem cells / Survival / Therapeutic targets / Tumor Microenvironment - drug effects / Tumors / Xenograft Model Antitumor Assays