Session: 603. Lymphoid Oncogenesis: Basic: Poster II
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Bleeding and Clotting, Lymphoid Leukemias, ALL, Translational Research, Combination therapy, Diseases, Therapies, Lymphoid Malignancies
Transcriptome analysis of mesenchymal cells in the BMM of mice with different leukemias had revealed annexin A2 (Anxa2), an initiator of fibrinolysis, to be differentially expressed. Using an ANXA2-deficient BMM as a model for impaired fibrinolysis, we showed that ANXA2 promotes the activation of plasmin, leading to decreased levels of the extracellular matrix (ECM) protein fibronectin in the BMM and accelerating the progression of BCR-ABL1+ B-cell acute lymphoblastic (B-ALL), but not MLL-AF9+ acute myeloid leukemia. Consistently, induction of B-ALL in tPA-deficient mice led to fibronectin accumulation in the BMM and significant survival prolongation.
The dense ECM in an ANXA2-deficient BMM is shown to entrap insulin-like growth factor (IGF) and to specifically reduce mTORC2-dependent signalling and proliferation in B-ALL cells. Conversely, B-ALL cell-derived interleukin (IL)-6 conditions hepatic generation of plasminogen, the precursor of plasmin, perpetuating this circuit. Treatment with -aminocaproic acid (EACA), an anti-hemorrhagic drug, which inhibits plasmin activation, reduces tumor burden and prolongs survival in syngeneic and xenogeneic murine models via increased fibronectin in the BMM. Human data confirm that IGF1 and fibronectin staining in trephine biopsies are correlated and that the mTORC2 pathway is distinctly activated in B-ALL. Higher expression of SERPINF2 (α2-antiplasmin), an inhibitor of plasmin, in human B-ALL cells leads to superior outcome. In summary, B-ALL-derived IL-6 impacts hepatic generation of fibrinolytic agents influencing B-ALL progression via ECM remodeling and regulation of the availability of B-ALL-supportive growth factors. Inhibition of plasmin-mediated degradation of the ECM by EACA may be beneficial as adjunct therapy in B-ALL.
Disclosures: No relevant conflicts of interest to declare.