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  • Freier Vortrag
  • VS-12-3

Hijacking of the fibrinolytic system by B-cell acute lymphoblastic leukaemia and its therapeutic targeting

Appointment

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MOA 01+02

Session

Hemostaseology

Topic

  • Hemostaseology

Authors

Dr. Valentina Minciacchi (Frankfurt a. M./ DE), Christina Karantanou (Frankfurt a. M./ DE), Costanza Zanetti (Frankfurt a. M./ DE), Dr. Rahul Kumar (Frankfurt a. M./ DE), Theresa Krack (Frankfurt a. M./ DE), Nathalie Thomasberger (Frankfurt a. M./ DE), Dr. Pablo Llavona (Frankfurt a. M./ DE), Prof. Dr. Sylvia Hartmann (Frankfurt a. M./ DE), Dr. Veronique Maguer-Satta (Lyon/ FR), Dr. Sylvain Lefort (Lyon/ FR), Dr. Mateusz Putyrski (Frankfurt a. M./ DE), Dr. Andreas Ernst (Frankfurt a. M./ DE), Dr. Brian Huntly (Cambridge/ GB), Dr. Eshwar Meduri (Cambridge/ GB), Prof. Dr. Daniela S. Krause (Frankfurt a. M./ DE)

Abstract

Background

The fibrinolytic system consists of the proenzyme plasminogen and its active form, plasmin, a serine protease. The activation of plasmin is tightly regulated by activators such as tissue plasminogen activator (tPA) and various inhibitors. A role of this plasminogen activation system in the microenvironment of solid tumours is being unravelled, but a function of this pathway in the bone marrow microenvironment (BMM), where haematological cancers usually originate, has so far been elusive.

Methods

We employed the retroviral transduction/transplantation model of B-cell acute lymphoblastic leukaemia (B-ALL), mice deficient for annexin A2 (ANXA2), a calcium-binding protein, which is also found in a complex with the plasminogen receptor protein, S100A10, and various in vitro assays including modeling of the extracellular matrix (ECM) to show the role of degradation of the ECM for B-ALL progression.

Results

ANXA2 was shown to be essential for plasmin activation and remodeling of the ECM in the BMM, thereby shortening survival in B-ALL. Induction of B-ALL in tPA-deficient mice led to fibronectin accumulation in the BMM and significant survival prolongation. Increased ECM density due to ANXA2 deficiency resulted in an entrapment of growth factors such as insulin-like growth factor 1, altering downstream signaling in B-ALL cells. Secretion of interleukin (IL)-6 by B-ALL cells increased hepatic generation of plasminogen/plasmin/tPA. Therapeutically, inhibition of plasmin activation by ε-aminocaproic acid (EACA), an anti-hemorrhagic drug, in murine models of B-ALL led to survival prolongation and fibronectin accumulation in the BMM.

Conclusion

Our data suggest that B-ALL cells condition their environment by increasing plasminogen/plasmin generation in the liver by IL-6, thereby, influencing the remodeling of ECM proteins in the BMM and, ultimately, B-ALL progression. We propose that inhibition of plasmin-mediated degradation of the ECM by EACA may be beneficial as an adjunct therapy for B-ALL.

Offenlegung Interessenkonflikt:

We declare no relevant conflicts of interest.

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