title: Increased μ-Calpain Activity in Blasts of Common B-Precursor Childhood Acute Lymphoblastic Leukemia Correlates with Their Lower Susceptibility to Apoptosis.
abstract: Childhood acute lymphoblastic leukemia (ALL) blasts are characterized by inhibited apoptosis promoting fast disease progress. It is known that in chronic lymphocytic and acute myeloid leukemias the reduced apoptosis is strongly related with the activity of calpain-calpastatin system (CCS) composed of cytoplasmic proteases--calpains--performing the modulatory proteolysis of key proteins involved in cell proliferation and apoptosis, and of their endogenous inhibitor--calpastatin. Here, the CCS protein abundance and activity was for the first time studied in childhood ALL blasts and in control bone marrow CD19+ B cells by semi-quantitative flow cytometry and western blotting of calpastatin fragments resulting from endogenous calpain activity. Significantly higher μ-calpain (CAPN1) gene transcription, protein amounts and activity (but not those of m-calpain), with calpastatin amount and transcription of its gene (CAST) greatly varying were observed in CD19(+) ALL blasts compared to control cells. Significant inverse relation between the amount/activity of calpain and spontaneous apoptosis was noted. Patients older than 10 years (considered at higher risk) displayed increased amounts and activities of blast calpain. Finally, treatment of blasts with the tripeptide calpain inhibitors II and IV significantly and in dose-dependent fashion increased the percentage of blasts entering apoptosis. Together, these findings make the CCS a potential new predictive tool and therapeutic target in childhood ALL.
authors: Department of Pathophysiology, Medical University of Gdańsk, Gdańsk, Poland.
authors: Anna
authors: A
authors: Mikosik
authors: Department of Pathology and Experimental Rheumatology, Medical University of Gdańsk, Gdańsk, Poland.
authors: Izabella
authors: I
authors: Henc
authors: Department of Pathology and Experimental Rheumatology, Medical University of Gdańsk, Gdańsk, Poland.
authors: Katarzyna
authors: K
authors: Ruckemann-Dziurdzińska
authors: Department of Pathophysiology, Medical University of Gdańsk, Gdańsk, Poland.
authors: Joanna E
authors: JE
authors: Frąckowiak
authors: Clinic of Pediatrics, Hematology and Oncology, Medical University of Gdańsk, Gdańsk, Poland.
authors: Anna
authors: A
authors: Płoszyńska
authors: Clinic of Pediatrics, Hematology and Oncology, Medical University of Gdańsk, Gdańsk, Poland.
authors: Anna
authors: A
authors: Balcerska
authors: Department of Pathology and Experimental Rheumatology, Medical University of Gdańsk, Gdańsk, Poland.
authors: Ewa
authors: E
authors: Bryl
authors: Department of Pathophysiology, Medical University of Gdańsk, Gdańsk, Poland.
authors: Jacek M
authors: JM
authors: Witkowski
mesh_terms: D000293:Adolescent; D000367:Age Factors; D017209:Apoptosis; D001402:B-Lymphocytes / Q000201:enzymology* / Q000473:pathology; D001752:Blast Crisis / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology
chemical_list: D009363:Neoplasm Proteins; D009842:Oligopeptides; C069861:calpain inhibitor 2; D002154:Calpain; C484806:CAPN1 protein, human