Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression.
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.
Bueno
María J
MJ
Cell Division and Cancer Group, Centro Nacional de Investigaciones Oncológicas (CNIO), E-28029 Madrid, Spain.
Pérez de Castro
Ignacio
I
Gómez de Cedrón
Marta
M
Santos
Javier
J
Calin
George A
GA
Cigudosa
Juan C
JC
Croce
Carlo M
CM
Fernández-Piqueras
José
J
Malumbres
Marcos
M
D020413:3' Untranslated Regions; D000818:Animals; D001374:Azacitidine / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002883:Chromosomes, Human, Pair 14; D033481:Chromosomes, Mammalian; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019656:Loss of Heterozygosity; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010654:Phenylbutyrates / Q000494:pharmacology; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D014916:Whole-Body Irradiation
D020413:3' Untranslated Regions; D004791:Enzyme Inhibitors; D035683:MicroRNAs; D010654:Phenylbutyrates; C406060:abl-bcr fusion protein, human; C075773:4-phenylbutyric acid; D015254:DNA Modification Methylases; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl; D001374:Azacitidine