Abstract
In our previous study, while chronic lymphocytic leukemia (CLL) cases showed higher levels of B and T lymphocyte attenuator (BTLA) mRNA compared to controls, lower BTLA protein expression was observed in cases compared to controls. Hence we hypothesize that micro RNA (miR) 155-5p regulates BTLA expression in CLL. In line with earlier data, expression of BTLA mRNA and miR-155-5p is elevated in CLL (p = 0.034 and p = 0.0006, respectively) as well as in MEC-1 cell line (p = 0.009 and 0.016, respectively). Inhibition of miR-155-5p partially restored BTLA protein expression in CLL patients (p = 0.01) and in MEC-1 cell lines (p = 0.058). Additionally, we aimed to evaluate the significance of BTLA deficiency in CLL cells on proliferation and IL-4 production of B cells. We found that secretion of IL-4 is not dependent on BTLA expression, since fractions of BTLA positive and BTLA negative B cells expressing intracellular IL-4 were similar in CLL patients and controls. We demonstrated that in controls the fraction of proliferating cells is lower in BTLA positive than in BTLA negative B cells (p = 0.059), which was not observed in CLL. However, the frequency of BTLA positive Ki67+ B cells in CLL was higher compared to corresponding cells from controls (p = 0.055) while there were no differences between the examined groups regarding frequency of BTLA negative Ki67+ B cells. Our studies suggest that miR-155-5p is involved in BTLA deficiency, affecting proliferation of CLL B cells, which may be one of the mechanisms responsible for CLL pathogenesis.
Highlights
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries, accounting for approximately 70% of all lymphoid leukemias
The 30 UTR region of the human B and T lymphocyte attenuator (BTLA) mRNA was predicted to be the target of micro RNA (miR)-155-5p
As we showed previously [18] mRNA BTLA expression was about 6-fold higher in CLL patients than in healthy controls (HC)
Summary
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries, accounting for approximately 70% of all lymphoid leukemias. According to the latest data in the United States, the age-adjusted incidence is 4.1 per 100,000 inhabitants. Incidence increases with age to 12.8 per 100,000 in those who are 65 years and older. The mean age of CLL diagnosis is 72 years, and is 1.5–2 times more common in men than women [1]. CLL is characterized by the gradual accumulation of mature B cells expressing. B-lineage-specific markers (CD19, CD20, CD23, and CD5 antigen) in lymphoid tissues, bone marrow, and peripheral blood (PB). The leukemic transformation is initiated by specific genomic alterations increasing the resistance of B cells against apoptosis. A number of genetic and epigenetic abnormalities are observed in CLL patients such as deletions of chromosomes 13, 11, 17, and trisomy 12; numerous somatic and gene copy number mutations, mainly NOTCH1, POT1, PTPN11, TP53, ATM and numerous epigenetic abnormalities related to micro-RNA regulation (reviewed in [1])
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