Abstract
The mammalian genome contains several hundred microRNAs that regulate gene expression through modulation of target mRNAs. Here, we report a fragile chromosomal region lost in specific hematopoietic malignancies. This 7 Mb region encodes about 12% of all genomic microRNAs, including miR-203. This microRNA is additionally hypermethylated in several hematopoietic tumors, including chronic myelogenous leukemias and some acute lymphoblastic leukemias. A putative miR-203 target, ABL1, is specifically activated in these hematopoietic malignancies in some cases as a BCR-ABL1 fusion protein (Philadelphia chromosome). Re-expression of miR-203 reduces ABL1 and BCR-ABL1 fusion protein levels and inhibits tumor cell proliferation in an ABL1-dependent manner. Thus, miR-203 functions as a tumor suppressor, and re-expression of this microRNA might have therapeutic benefits in specific hematopoietic malignancies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions
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Animals
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Azacitidine / pharmacology
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Cell Line, Tumor
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Cell Proliferation* / drug effects
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Chromosomes, Human, Pair 14
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Chromosomes, Mammalian
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DNA Methylation*
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DNA Modification Methylases / antagonists & inhibitors
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DNA Modification Methylases / metabolism
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Enzyme Inhibitors / pharmacology
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Fusion Proteins, bcr-abl / metabolism*
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Gene Expression Profiling
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Gene Expression Regulation, Leukemic
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Gene Expression Regulation, Neoplastic* / drug effects
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Gene Silencing*
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Humans
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
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Loss of Heterozygosity
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Lymphoma, T-Cell / genetics
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Lymphoma, T-Cell / metabolism
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Lymphoma, T-Cell / pathology
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Lymphoproliferative Disorders / enzymology
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Lymphoproliferative Disorders / genetics
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Lymphoproliferative Disorders / metabolism*
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Lymphoproliferative Disorders / pathology
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Mice
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Mice, Inbred C57BL
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Phenylbutyrates / pharmacology
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Philadelphia Chromosome
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Promoter Regions, Genetic
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Proto-Oncogene Proteins c-abl / metabolism*
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Time Factors
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Transfection
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Up-Regulation
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Whole-Body Irradiation
Substances
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3' Untranslated Regions
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Enzyme Inhibitors
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MicroRNAs
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Phenylbutyrates
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abl-bcr fusion protein, human
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4-phenylbutyric acid
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DNA Modification Methylases
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Fusion Proteins, bcr-abl
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Proto-Oncogene Proteins c-abl
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Azacitidine
Associated data
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GEO/GSE10858
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GEO/GSE10859
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GEO/GSE10861