PB0712 - Establishment of mouse xenograft and allograft models of acute promyelocytic leukemia and role of tissue factor in the activation of coagulation

Background: Acute promyelocytic leukemia (APL) is associated with the activation of coagulation, thrombocytopenia, hyperfibrinolysis and fatal intracranial bleeding. The precise mechanisms of APL-induced bleeding have not been fully understood.

Aims: To determine the role of tissue factor (TF) in the activation of coagulation in mouse xenograft and allograft models of APL.

Methods: We established a mouse xenograft model of APL by intravenously injecting 4 million NB4 cells (a human APL cell line) into NSG mice. We also established a mouse allograft model of APL by intraperitoneally injecting 1 million splenocytes from transgenic mice that spontaneously develop APL (Rara+/- x mCG-PML-RARA+/-) into C57BL6 mice. Levels of platelets, thrombin-antithrombin (TAT) complexes, D-dimer, plasmin-antiplasmin (PAP) complex, soluble (s) P-selectin, and sE-selectin were measured. A tail transection model and a collagenase-induced intracranial bleeding model were used. An inhibitory anti-human TF antibody (HTF-1) and an inhibitory anti-mouse TF antibody (1H1) were injected into mice to inhibit human and mouse TF, respectively.

Results: Both the mouse xenograft and allograft models of APL had increased TAT complexes, D-dimer and PAP complexes indicating activation of coagulation and fibrinolysis. In addition, decreased platelet counts and increased sP-selectin levels but not sE-selectin levels were observed in both models. The two models of APL had prolonged tail bleeding time and increased brain bleeding lesions. We observed spontaneous intracranial bleeding in a mouse bearing murine APL cells that died. Importantly, HTF-1 significantly decreased TAT levels in the xenograft model of APL and 1H1 significantly decreased TAT levels in the allograft model of APL.

Conclusion(s): Both the mouse xenograft and allograft models of APL had the activation of coagulation, thrombocytopenia, hyperfibrinolysis and bleeding that mimic human APL. APL cell-derived TF is a major activator of coagulation in the mouse xenograft model of APL. TF contributed to the activation of coagulation in the mouse allograft models of APL.