Excessive amount and activity of μ-calpain affects apoptotic machinery in chronic B-cell leukemia cells and influences the course of the disease

  • Paulina Łopatniuk Department of Pathophysiology, Medical University of Gdansk, Gdańsk, Poland
  • Zofia Puchalska Department of Pathophysiology, Medical University of Gdansk, Gdańsk, Poland
  • Andrzej Mital Department of Hematology, Medical University of Gdansk, Gdańsk, Poland
  • Anna Mikosik Department of Pathophysiology, Medical University of Gdansk, Gdańsk, Poland
  • Joanna Frąckowiak Department of Pathophysiology, Medical University of Gdansk, Gdańsk, Poland
  • Andrzej Hellmann Department of Hematology, Medical University of Gdansk, Gdańsk, Poland
  • Agnieszka Daca Department of Pathology and Experimental Rheumatology, Medical University of Gdansk, Gdańsk, Poland
  • Ewa Bryl Department of Pathology and Experimental Rheumatology, Medical University of Gdansk, Gdańsk, Poland
  • Tamas Fulop Department of Medicine, Geriatric Division, Research Center on Aging, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
  • Jacek M. Witkowski Gdańsk Medical University, Gdańsk, Poland https://orcid.org/0000-0003-2906-1109

Abstract

B-cell Chronic Lymphocytic Leukemia (B-CLL) is the most common hematological disorder among middle-aged/elderly people in the Western countries. We have shown earlier that B-CLL cells exhibit elevated total amount and available activity of µ-calpain, belonging to a family of ubiquitous, strongly Ca-dependent proteases, involved in the control of proliferation and apoptosis. In this study we attempted to estimate a potential clinical value of μ-calpain in relation to B-CLL clinical staging in patients with extremely high lymphocytosis and studied the molecular mechanisms associating calpain activity with clinical progress of the disease. We observed significant correlations between the amounts of intracellular μ-calpain and clinical staging of the disease, with RAI stage 1 corresponding to the highest calpain amounts in the leukemic cells. There was also a positive, statistically significant correlation between the amount of μ-calpain and phosphorylated (p)ZAP-70 in B-CLL lymphocytes. Calpain activity in the B-CLL cells is associated with decreased activities of pro-apoptotic caspases -3 and -9, and reciprocally with an increased amount of anti-apoptotic Bcl-2. Together, all of these findings make calpain activity in B-CLL cells a promising target modifying the properties of these cells and facilitating therapy. Finally, the proportion of CD19+ B cells with elevated μ-calpain and pZap-70 was markedly reduced in patients after successful therapy.

Published
2020-06-16
Section
Articles