BTLA Expression in CLL: Epigenetic Regulation and Impact on CLL B Cell Proliferation and Ability to IL-4 Production
Lidia Karabon,
Anna Andrzejczak,
Lidia Ciszak,
Anna Tomkiewicz,
Aleksandra Szteblich,
Agnieszka Bojarska-Junak,
Jacek Roliński,
Dariusz Wołowiec,
Tomasz Wróbel,
Agata Kosmaczewska
Affiliations
Lidia Karabon
Laboratory of Genetics and Epigenetics of Human Diseases, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigl 12 Str., 53-114 Wroclaw, Poland
Anna Andrzejczak
Laboratory of Genetics and Epigenetics of Human Diseases, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigl 12 Str., 53-114 Wroclaw, Poland
Lidia Ciszak
Laboratory of Immunopathology, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigl 12 Str., 53-114 Wroclaw, Poland
Anna Tomkiewicz
Laboratory of Genetics and Epigenetics of Human Diseases, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigl 12 Str., 53-114 Wroclaw, Poland
Aleksandra Szteblich
Laboratory of Immunopathology, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigl 12 Str., 53-114 Wroclaw, Poland
Agnieszka Bojarska-Junak
Department of Clinical Immunology, Medical University of Lublin, ul. Chodźki 4a, 20-093 Lublin, Poland
Jacek Roliński
Department of Clinical Immunology, Medical University of Lublin, ul. Chodźki 4a, 20-093 Lublin, Poland
Dariusz Wołowiec
Department and Clinic of Hematology, Blood Neoplasms, and Bone Marrow Transplantation, Medical University, Wybrzeże Ludwika Pasteura 4, 50-367 Wroclaw, Poland
Tomasz Wróbel
Department and Clinic of Hematology, Blood Neoplasms, and Bone Marrow Transplantation, Medical University, Wybrzeże Ludwika Pasteura 4, 50-367 Wroclaw, Poland
Agata Kosmaczewska
Laboratory of Immunopathology, Department of Experimental Therapy, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigl 12 Str., 53-114 Wroclaw, Poland
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.
