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

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, multi...

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Veröffentlicht in:Archives of medical research Jg. 56; H. 3; S. 103124
Hauptverfasser: Golovina, Elena, Kokavec, Juraj, Kazantsev, Dmitry, Yurikova, Oxana, Bajecny, Martin, Savvulidi, Filipp Georgijevic, Simersky, Radim, Lenobel, Rene, Tost, Jorg, Herynek, Vit, Sefc, Ludek, Sebela, Marek, Klener, Pavel, Zemanova, Zuzana, Stopka, Tomas, Vargova, Karina Savvulidi
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Elsevier Inc 01.04.2025
Elsevier
Schlagworte:
B-cells
Biochemistry, Molecular Biology
Carrier Proteins - genetics
Carrier Proteins - metabolism
Cell cycle
Cell Cycle Checkpoints - genetics
Cell Line, Tumor
Cell Proliferation - genetics
CRISPR/Cas9
Cyclin D1 - genetics
Cyclin D1 - metabolism
Cyclin-Dependent Kinase Inhibitor p21 - genetics
Cyclin-Dependent Kinase Inhibitor p21 - metabolism
Gene Expression Regulation, Leukemic
Genomics
Heat-Shock Proteins
Humans
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell - genetics
Leukemia, Lymphocytic, Chronic, B-Cell - pathology
Life Sciences
MicroRNAs - genetics
MicroRNAs - metabolism
miR-155
B-cells
CRISPR/Cas9
miR-155
Leukemia
Cell cycle
miR-155 CRISPR/Cas9 Cell cycle B-cells Leukemia
ISSN:0188-4409, 1873-5487, 1873-5487
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Zusammenfassung: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. 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. 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). 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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:0188-4409
1873-5487
1873-5487
DOI:10.1016/j.arcmed.2024.103124