Plasminogen activation in human acute leukaemias

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Plasminogen activation is crucial for solid tumor progression.
• Its role in leukemia, particularly in leukaemic cell invasion and spread, remains largely unexplored.
• Understanding these pathways is vital for novel therapeutic strategies.

Purpose of the Study:

• To investigate the production of plasminogen activators (urokinase [uPA] and tissue-type PA [tPA]), their receptor (uPAR), and inhibitors (PAI-1 and PAI-2) by leukaemic cells.
• To determine the specific subtypes of acute myeloid leukaemia (AML) and acute lymphoid leukaemia (ALL) involved in this production.
• To elucidate the potential contribution of plasminogen activation to leukaemic cell behavior and fibrinolytic imbalance.

Main Methods:

• Analysis of mRNA content and enzymatic activities in leukaemic cells from 37 patients (26 AML, 11 ALL).
• Detection of uPA, tPA, uPAR, PAI-1, and PAI-2 using molecular and enzymatic assays.
• SDS-PAGE/zymography to confirm active uPA production in cell extracts and supernatants.

Main Results:

• High uPA mRNA levels were detected in AML subtypes M1, M2, M3, and M4-M5; tPA mRNA was absent in all cases.
• uPAR mRNA was found in M4-M5 AML subtypes, PAI-1 in M3 and M4-M5, and PAI-2 predominantly in M2 and M4-M5.
• Active uPA production was confirmed in AML cells (primarily M4-M5) but not in ALL cells.

Conclusions:

• Leukaemic cells, particularly certain AML subtypes, synthesize uPA, uPAR, PAI-1, and PAI-2.
• Plasminogen activation system components likely contribute to leukaemic cell invasion and fibrinolytic imbalance.
• The interaction of uPA with uPAR may influence M4-M5 AML differentiation and proliferation.