Suppression of the let-7b microRNA pathway by DNA hypermethylation in infant acute lymphoblastic leukemia with MLL gene rearrangements
| Autor: | Takeshi Inukai, Zhouying Wu, Minenori Eguchi-Ishimae, Wenming Gao, Masanori Nishi, Mariko Eguchi, Yuhei Hamasaki, Kanji Sugita, Sanae Kawakami, Hisamichi Tauchi, Eiichi Ishii, Hidehiko Iwabuki |
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| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
Antimetabolites Antineoplastic Oncogene Proteins Fusion Molecular Sequence Data Biology Real-Time Polymerase Chain Reaction Fusion gene hemic and lymphatic diseases microRNA medicine Tumor Cells Cultured Humans RNA Messenger Promoter Regions Genetic Cell Proliferation Regulation of gene expression Gene Rearrangement Base Sequence Gene Expression Regulation Leukemic Reverse Transcriptase Polymerase Chain Reaction Infant Hematology Gene rearrangement Histone-Lysine N-Methyltransferase DNA Methylation Precursor Cell Lymphoblastic Leukemia-Lymphoma medicine.disease Molecular biology Fusion protein Infant Acute Lymphoblastic Leukemia Leukemia MicroRNAs Oncology Cancer research Azacitidine Myeloid-Lymphoid Leukemia Protein |
| Zdroj: | Leukemia. 27(2) |
| ISSN: | 1476-5551 |
| Popis: | MicroRNAs (miRNAs) regulate cell proliferation and differentiation by controlling the expression of proteins involved in many signaling pathways. Recent studies have shown that dysregulation of miRNA expression is associated with increased tumorigenicity and a poor prognosis in several types of cancers. The miRNA let-7b is one of the severely downregulated miRNAs in mixed-lineage leukemia (MLL)-rearranged acute lymphoblastic leukemia (ALL) patients. In vitro transfection of leukemogenic MLL fusion genes into human embryonic kidney-293 cells suppressed let-7b expression. In leukemic cells with an MLL fusion gene, the regulatory region for let-7b expression was hypermethylated, and its expression was partially recovered after culturing the cells with the demethylating agent 5-azacitidine. These results suggest that loss of let-7b expression may be one of the consequences of oncogenic MLL fusion proteins, and contributes to leukemogenesis possibly through the upregulation of let-7b-regulated target genes with leukemogenic potential in hematopoietic cells. The enforced expression of let-7b in ALL cell lines with an MLL fusion gene inhibited their growth, indicating the possible use of let-7b as a new therapeutic tool for refractory infant ALL with an MLL fusion gene. |
| Databáze: | OpenAIRE |
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