Exploitation of the fibrinolytic system by B-cell acute lymphoblastic leukemia and its therapeutic targeting
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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-11-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54361-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849221101290258432 |
|---|---|
| author | 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 Daniela S. Krause |
| author_facet | 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 Daniela S. Krause |
| author_sort | Valentina R. Minciacchi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b12036d37cd94e1e9d6b5fe68f4e452e |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b12036d37cd94e1e9d6b5fe68f4e452e2024-11-24T12:32:46ZengNature PortfolioNature Communications2041-17232024-11-0115111910.1038/s41467-024-54361-4Exploitation of the fibrinolytic system by B-cell acute lymphoblastic leukemia and its therapeutic targetingValentina R. Minciacchi0Jimena Bravo1Christina Karantanou2Raquel S. Pereira3Costanza Zanetti4Rahul Kumar5Nathalie Thomasberger6Pablo Llavona7Theresa Krack8Katrin Bankov9Melanie Meister10Sylvia Hartmann11Véronique Maguer-Satta12Sylvain Lefort13Mateusz Putyrski14Andreas Ernst15Brian J. P. Huntly16Eshwar Meduri17Wolfram Ruf18Daniela S. Krause19Center for Thrombosis and Hemostasis (CTH), Johannes Gutenberg University Medical CenterInstitute of Transfusion Medicine – Transfusion Center, Johannes Gutenberg University Medical CenterDepartment of Vascular Dysfunction - Medical Faculty Mannheim of Heidelberg UniversityInstitute for Experimental Pediatric Hematology and Oncology, Goethe-University FrankfurtDivision of mRNA Cancer Immunotherapy, Helmholtz Institute for Translational Oncology MainzInstitute of Transfusion Medicine – Transfusion Center, Johannes Gutenberg University Medical CenterBioNTech SEThe Institute of Molecular BiologyInstitute of Transfusion Medicine – Transfusion Center, Johannes Gutenberg University Medical CenterDepartment of Pediatrics (Hematology/Oncology), Charité-UniversitätsmedizinAbbVieDepartment of Pathology, Goethe UniversityCRCL, Inserm U1052-CNRS UMR5286, Centre Léon BérardCRCL, Inserm U1052-CNRS UMR5286, Centre Léon BérardFraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMPPharmazentrum/ZAFES Frankfurt, Faculty of Medicine, Goethe-University FrankfurtDepartment of Haematology, University of CambridgeDepartment of Haematology, University of CambridgeCenter for Thrombosis and Hemostasis (CTH), Johannes Gutenberg University Medical CenterInstitute of Transfusion Medicine – Transfusion Center, Johannes Gutenberg University Medical CenterAbstract 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.https://doi.org/10.1038/s41467-024-54361-4 |
| spellingShingle | 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 Daniela S. Krause Exploitation of the fibrinolytic system by B-cell acute lymphoblastic leukemia and its therapeutic targeting Nature Communications |
| title | Exploitation of the fibrinolytic system by B-cell acute lymphoblastic leukemia and its therapeutic targeting |
| title_full | Exploitation of the fibrinolytic system by B-cell acute lymphoblastic leukemia and its therapeutic targeting |
| title_fullStr | Exploitation of the fibrinolytic system by B-cell acute lymphoblastic leukemia and its therapeutic targeting |
| title_full_unstemmed | Exploitation of the fibrinolytic system by B-cell acute lymphoblastic leukemia and its therapeutic targeting |
| title_short | Exploitation of the fibrinolytic system by B-cell acute lymphoblastic leukemia and its therapeutic targeting |
| title_sort | exploitation of the fibrinolytic system by b cell acute lymphoblastic leukemia and its therapeutic targeting |
| url | https://doi.org/10.1038/s41467-024-54361-4 |
| work_keys_str_mv | AT valentinarminciacchi exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT jimenabravo exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT christinakarantanou exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT raquelspereira exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT costanzazanetti exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT rahulkumar exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT nathaliethomasberger exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT pablollavona exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT theresakrack exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT katrinbankov exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT melaniemeister exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT sylviahartmann exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT veroniquemaguersatta exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT sylvainlefort exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT mateuszputyrski exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT andreasernst exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT brianjphuntly exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT eshwarmeduri exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT wolframruf exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting AT danielaskrause exploitationofthefibrinolyticsystembybcellacutelymphoblasticleukemiaanditstherapeutictargeting |