Roy Chowdhury 2020 Cancers (Basel)

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Roy Chowdhury S, Bouchard EDJ, Saleh R, Nugent Z, Peltier C, Mejia E, Hou S, McFall C, Squires M, Hewitt D, Davidson L, Shen GX, Johnston JB, Doucette C, Hatch GM, Fernyhough P, Marshall A, Gibson SB, Dawe DE, Banerji V (2020) Mitochondrial respiration correlates with prognostic markers in chronic lymphocytic leukemia and Is normalized by ibrutinib treatment. Cancers (Basel) 12:E650.

» PMID: 32168755 Open Access

Roy Chowdhury S, Bouchard EDJ, Saleh R, Nugent Z, Peltier C, Mejia E, Hou S, McFall C, Squires M, Hewitt D, Davidson L, Shen GX, Johnston JB, Doucette C, Hatch GM, Fernyhough P, Marshall A, Gibson SB, Dawe DE, Banerji V (2020) Cancers (Basel)

Abstract: Mitochondrial bioenergetics profiling, a measure of oxygen consumption rates, correlates with prognostic markers and can be used to assess response to therapy in chronic lymphocytic leukemia (CLL) cells. In this study, we measured mitochondrial respiration rates in primary CLL cells using respirometry to evaluate mitochondrial function. We found significant increases in mitochondrial respiration rates in CLL versus control B lymphocytes. We also observed amongst CLL patients that advanced age, female sex, zeta-chain-associated protein of 70 kD (ZAP-70+), cluster of differentiation 38 (CD38+), and elevated β2-microglobulin (β2-M) predicted increased maximal respiration rates. ZAP-70+ CLL cells exhibited significantly higher bioenergetics than B lymphocytes or ZAP-70- CLL cells and were more sensitive to the uncoupler, carbonyl cyanide-p-trifluoro-methoxyphenylhydrazone (FCCP). Univariable and multivariable linear regression analysis demonstrated that ZAP-70+ predicted increased maximal respiration. ZAP-70+ is a surrogate for B cell receptor (BCR) activation and can be targeted by ibrutinib, which is a clinically approved Bruton's tyrosine kinase (BTK) inhibitor. Therefore, we evaluated the oxygen consumption rates (OCR) of CLL cells and plasma chemokine (C-C motif) ligands 3 and 4 (CCL3/CCL4) levels from ibrutinib-treated patients and demonstrated decreased OCR similar to control B lymphocytes, suggesting that ibrutinib treatment resets the mitochondrial bioenergetics, while diminished CCL3/CCL4 levels indicate the down regulation of the BCR signaling pathway in CLL. Our data support evaluation of mitochondrial respiration as a preclinical tool for the response assessment of CLL cells.

Keywords: B cell receptor, CCL3/Oroboros oxygraph, ZAP-70, Chronic lymphocytic leukemia, Ibrutinib, Mitochondria, Oxygen consumption rates Bioblast editor: Plangger M O2k-Network Lab: CA Winnipeg Banerji V, CA Winnipeg Fernyhough P


Labels: MiParea: Respiration, Patients  Pathology: Cancer 

Organism: Human  Tissue;cell: Lymphocyte  Preparation: Intact cells 


Coupling state: LEAK, ET  Pathway: ROX  HRR: Oxygraph-2k 

2020-03