title: Methylation-mediated repression of microRNA-143 enhances MLL-AF4 oncogene expression.
abstract: Fusion proteins containing the amino terminus of mixed lineage leukemia (MLL) are common in acute lymphoblastic leukemia (ALL) due to translocations. The MLL-AF4 fusion protein is generated by the translocation t(4;11)(q21;q23), and t(4;11)-positive ALL patients (MLL-AF4 ALL), have a notoriously poorer prognosis compared with patients with other MLL-associated leukemias. The detailed role of this fusion protein in leukemogenesis is not well understood. MicroRNAs (miRNAs) targeting the AF4 3' untranslated regions may modulate MLL-AF4 fusion protein levels, raising the question of whether regulation of these miRNAs are involved in the progression of MLL-AF4 ALL. In this study, we show that miR-143 was identified as a regulator of MLL-AF4 expression in MLL-AF4 ALL samples. Restoration of miR-143 in MLL-AF4-positive RS4;11 and MV4-11 cells induced apoptosis, negatively contributing to leukemia cell growth by reducing MLL-AF4 fusion protein levels. Furthermore, miR-143 was epigenetically repressed by promoter hypermethylation in MLL-AF4-positive primary blasts and cell lines, but not in normal bone marrow cells and MLL-AF4-negative primary blasts, which was directly associated with expression of the MLL-AF4 oncogene. This is the first study to show that miR-143 functions as a tumor suppressor in MLL-AF4 B-cell ALL. These data reveal the therapeutic promise of upregulating miR-143 expression for MLL-AF4 B-cell ALL.
authors.affiliation: Department of Hematology, Chinese PLA General Hospital, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Dou
authors.forename: D
authors.initials: D
authors.lastname: Zheng
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: L
authors.initials: L
authors.lastname: Gao
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: L
authors.initials: L
authors.lastname: Yu
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019175:DNA Methylation; D015536:Down-Regulation; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D015448:Leukemia, B-Cell / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D011519:Proto-Oncogenes
chemical_list: C115962:HOXA7 protein, human; D018398:Homeodomain Proteins; C542359:MIRN143 microRNA, human; C113855:MLL-AF4 fusion protein, human; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion; C097899:homeobox protein HOXA9; D051788:Myeloid-Lymphoid Leukemia Protein