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Deficiency of miR-155 in Leukemic B-Cells Results in Cell Cycle Arrest and Deregulation of MIR155HG/TP53INP1/CDKN1A/CCND1 network

E. Golovina, J. Kokavec, D. Kazantsev, O. Yurikova, M. Bajecny, FG. Savvulidi, R. Simersky, R. Lenobel, J. Tost, V. Herynek, L. Sefc, M. Sebela, P. Klener, Z. Zemanova, T. Stopka, KS. Vargova

. 2025 ; 56 (3) : 103124. [pub] 20241125

Jazyk angličtina

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc25016307

BACKGROUND: Cell cycle progression and leukemia development are tightly regulated processes in which even a small imbalance in the expression of cell cycle regulatory molecules and microRNAs (miRNAs) can lead to an increased risk of cancer/leukemia development. Here, we focus on the study of a ubiquitous, multifunctional, and oncogenic miRNA-hsa-miR-155-5p (miR-155, MIR155HG), which is overexpressed in malignancies including chronic lymphocytic leukemia (CLL). Nonetheless, the precise mechanism of how miR-155 regulates the cell cycle in leukemic cells remains the subject of extensive research. METHODS: We edited the CLL cell line MEC-1 by CRISPR/Cas9 to introduce a short deletion within the MIR155HG gene. To describe changes at the transcriptome and miRNome level in miR-155-deficient cells, we performed mRNA-seq/miRNA-seq and validated changes by qRT-PCR. Flow cytometry was used to measure cell cycle kinetics. A WST-1 assay, hemocytometer, and Annexin V/PI staining assessed cell viability and proliferation. RESULTS: The limited but phenotypically robust miR-155 modification impaired cell proliferation, cell cycle, and cell ploidy. This was accompanied by overexpression of the negative cell cycle regulator p21/CDKN1A and Cyclin D1 (CCND1). We confirmed the overexpression of canonical miR-155 targets such as PU.1, FOS, SHIP-1, TP53INP1 and revealed new potential targets (FCRL5, ISG15, and MX1). CONCLUSIONS: We demonstrate that miR-155 deficiency impairs cell proliferation, cell cycle, transcriptome, and miRNome via deregulation of the MIR155HG/TP53INP1/CDKN1A/CCND1 axis. Our CLL model is valuable for further studies to manipulate miRNA levels to revert highly aggressive leukemic cells to nearly benign or non-leukemic types.

Citace poskytuje Crossref.org

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$a BACKGROUND: Cell cycle progression and leukemia development are tightly regulated processes in which even a small imbalance in the expression of cell cycle regulatory molecules and microRNAs (miRNAs) can lead to an increased risk of cancer/leukemia development. Here, we focus on the study of a ubiquitous, multifunctional, and oncogenic miRNA-hsa-miR-155-5p (miR-155, MIR155HG), which is overexpressed in malignancies including chronic lymphocytic leukemia (CLL). Nonetheless, the precise mechanism of how miR-155 regulates the cell cycle in leukemic cells remains the subject of extensive research. METHODS: We edited the CLL cell line MEC-1 by CRISPR/Cas9 to introduce a short deletion within the MIR155HG gene. To describe changes at the transcriptome and miRNome level in miR-155-deficient cells, we performed mRNA-seq/miRNA-seq and validated changes by qRT-PCR. Flow cytometry was used to measure cell cycle kinetics. A WST-1 assay, hemocytometer, and Annexin V/PI staining assessed cell viability and proliferation. RESULTS: The limited but phenotypically robust miR-155 modification impaired cell proliferation, cell cycle, and cell ploidy. This was accompanied by overexpression of the negative cell cycle regulator p21/CDKN1A and Cyclin D1 (CCND1). We confirmed the overexpression of canonical miR-155 targets such as PU.1, FOS, SHIP-1, TP53INP1 and revealed new potential targets (FCRL5, ISG15, and MX1). CONCLUSIONS: We demonstrate that miR-155 deficiency impairs cell proliferation, cell cycle, transcriptome, and miRNome via deregulation of the MIR155HG/TP53INP1/CDKN1A/CCND1 axis. Our CLL model is valuable for further studies to manipulate miRNA levels to revert highly aggressive leukemic cells to nearly benign or non-leukemic types.
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$a Kokavec, Juraj $u Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University, First Faculty of Medicine, Charles University, Vestec, Czech Republic
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$a Kazantsev, Dmitry $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
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$a Yurikova, Oxana $u Al-Farabi Kazakh National University, Faculty of Biology and Biotechnology, Almaty, Kazakhstan
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$a Bajecny, Martin $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic; The Center for Advanced Preclinical Imaging, First Faculty of Medicine, Charles University, Prague, Czech Republic
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$a Savvulidi, Filipp Georgijevic $u Department of Animal Science, Faculty of Agrobiology, Food and Natural Resources, Czech University, Prague, Kamýcká, Czech Republic
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$a Simersky, Radim $u Department of Chemical Biology, Faculty of Science, Palacký University, Olomouc, Czech Republic
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$a Lenobel, Rene $u Laboratory of Growth Regulators, Institute of Experimental Botany of the Czech Academy of Sciences and Palacký University, Olomouc, Czech Republic
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$a Tost, Jorg $u Centre National de Recherche en Génomique Humaine, CEA-Institut de Biologie Francois Jacob, Universite Paris-Saclay, Évry, France
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$a Herynek, Vit $u The Center for Advanced Preclinical Imaging, First Faculty of Medicine, Charles University, Prague, Czech Republic
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$a Sefc, Ludek $u The Center for Advanced Preclinical Imaging, First Faculty of Medicine, Charles University, Prague, Czech Republic
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$a Sebela, Marek $u Department of Biochemistry, Faculty of Science, Palacký University, Olomouc, Czech Republic
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$a Klener, Pavel $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic
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$a Zemanova, Zuzana $u Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital, First Faculty of Medicine, Charles University, Prague, Czech Republic
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$a Stopka, Tomas $u Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University, First Faculty of Medicine, Charles University, Vestec, Czech Republic
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