OC 29.3 - The fibrinolytic system in B-cell acute lymphoblastic leukemia and its targeting

Sunday, June 23, 2024

15:15 – 15:30 ICT

Room: 208 A-D

Presenting Author(s)

VM

Valentina R. Minciacchi, PhD

Postdoctoral fellow
Center for Thrombosis and Hemostasis (CTH), Johannes Gutenberg University Medical Center, Mainz
Mainz, Rheinland-Pfalz, Germany

Co-Author(s)

CK

Christina Karantanou

Postdoctoral Fellow
Department of Vascular Dysfunction, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University
Mannheim, Baden-Wurttemberg, Germany
CZ

Costanza Zanetti

Postdoctoral Fellow
Helmholtz Institute for Translational Oncology Mainz (HI-TRON Mainz)
Mainz, Rheinland-Pfalz, Germany
RK

Rahul Kumar

Postdoctoral Fellow
Institute of Transfusion Medicine - Transfusion Centre, Johannes Gutenberg University Medical Centre, Mainz
Mainz, Rheinland-Pfalz, Germany
TK

Theresa Krack

Lab Manager
Institute of Transfusion Medicine - Transfusion Centre, Johannes Gutenberg University Medical Centre, Mainz
Mainz, Rheinland-Pfalz, Germany
NT

Nathalie Thomasberger

M.Sc. Student
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main
Frankfurt am Main, Hessen, Germany
PL

Pablo Llavona

Staff Scientist
Institute of Molecular Biology, Mainz
Mainz, Rheinland-Pfalz, Germany
SH

Sylvia Hartman

Group Leader
Department of Pathology, Goethe University, Frankfurt am Main
Frankfurt am Main, Rheinland-Pfalz, Germany
VM

Véronique Maguer-Satta

Group Leader
CRCL, Inserm U1052-CNRS UMR5286, Centre Léon Bérard, Lyon
Lyon, Rhone-Alpes, France
SL

Sylvain Lefort

Group Leader
CRCL, Inserm U1052-CNRS UMR5286, Centre Léon Bérard, Lyon
Lyon, Rhone-Alpes, France
MP

Mateusz Putyrski

Postdoctoral Fellow
Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMP, Frankfurt am Main
Frankfurt am Main, Hessen, Germany
AE

Andreas Ernst

Group Leader
Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMP, Frankfurt am Main
Frankfurt am Main, Hessen, Germany
EM

Eshwar Meduri

Research Associate
Department of Haematology, University of Cambridge
Cambridge, England, United Kingdom
BH

Brian Huntly

Head of Department and Professor of Leukaemia Stem Cell Biology
Department of Haematology, University of Cambridge
Cambridge, England, United Kingdom
Wolfram Ruf

Scientific Director
Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz
Mainz, Rheinland-Pfalz, Germany
DK

Daniela S. Krause

Director
Institute of Transfusion Medicine - Transfusion Centre, Johannes Gutenberg University Medical Centre, Mainz
Mainz, Rheinland-Pfalz, Germany

Background: The fibrinolytic system contributes to the remodeling of the bone marrow (BM) microenvironment (BMM) and to the mobilization of hematopoietic stem cells. Furthermore, plasmin-mediated degradation of the extracellular matrix (ECM) can facilitate metastasis of solid tumors. However, the role of fibrinolysis in the BMM during leukemia progression is largely unknown. Our preliminary data revealed that annexin 2 (ANXA2), a facilitator of plasmin activation, is differentially expressed in the BMM of mice with different leukemias.

Aims: We hypothesized that plasmin generation plays a role in the progression of B-cell acute lymphoblastic leukemia (B-ALL) via remodeling the ECM within the BMM.

Methods: B-ALL was induced using the retroviral transduction/transplantation model. ANXA2-deficient mice and tissue plasminogen activator (tPA)-deficient mice were used as models for impaired fibrinolysis in the BMM. Primary stromal cells were isolated from the BM control and ANXA2-deficient mice to assess the role of plasmin generation in B-ALL.

Results: Deficiency of ANXA2 in the BMM led to accumulation of the ECM protein fibronectin and prolongation of survival in mice with B-ALL. Similar effects were observed in tPA-deficient mice. Consistently, administration of plasmin to ANXA2-defcient mice with B-ALL reversed the phenotype. Furthermore, mice with B-ALL showed increased hepatic production of plasminogen and higher levels of tPA in the BM. Accumulation of ECM was revealed to entrap insulin-like growth factor 1 and to reduce mTORC2-dependent signaling and proliferation in B-ALL cells. Treatment with ε-aminocaproic acid (EACA), which inhibits plasmin activation, resulted in prolongation of survival and increased fibronectin in the BMM. Finally, higher expression of a2-antiplasmin was observed to correlate with a better outcome in patients with B-ALL.

Conclusion(s): These results suggest that fibrinolysis is involved in ECM remodeling and growth factor availability during B-ALL progression and that inhibition of this process by EACA may be considered as adjunct therapy.