title: HMGA2 as a potential molecular target in KMT2A-AFF1-positive infant acute lymphoblastic leukaemia.
abstract: Acute lymphoblastic leukaemia (ALL) in infants is an intractable cancer in childhood. Although recent intensive chemotherapy progress has considerably improved ALL treatment outcome, disease cure is often accompanied by undesirable long-term side effects, and efficient, less toxic molecular targeting therapies have been anticipated. In infant ALL cells with KMT2A (MLL) fusion, the microRNA let-7b (MIRLET7B) is significantly downregulated by DNA hypermethylation of its promoter region. We show here that the expression of HMGA2, one of the oncogenes repressed by MIRLET7B, is reversely upregulated in infant ALL leukaemic cells, particularly in KMT2A-AFF1 (MLL-AF4) positive ALL. In addition to the suppression of MIRLET7B, KMT2A fusion proteins positively regulate the expression of HMGA2. HMGA2 is one of the negative regulators of CDKN2A gene, which encodes the cyclin-dependent kinase inhibitor p16(INK4A) . The HMGA2 inhibitor netropsin, when combined with demethylating agent 5-azacytidine, upregulated and sustained the expression of CDKN2A, which resulted in growth suppression of KMT2A-AFF1-expressing cell lines. This effect was more apparent compared to treatment with 5-azacytidine alone. These results indicate that the MIRLET7B-HMGA2-CDKN2A axis plays an important role in cell proliferation of leukaemic cells and could be a possible molecular target for the therapy of infant ALL with KMT2A-AFF1.
authors.affiliation: Department of Paediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Zhouying
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Paediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Minenori
authors.initials: M
authors.lastname: Eguchi-Ishimae
authors.affiliation: Department of Paediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yagi
authors.affiliation: Department of Paediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Iwabuki
authors.affiliation: Department of Paediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Wenming
authors.initials: W
authors.lastname: Gao
authors.affiliation: Department of Paediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Hisamichi
authors.initials: H
authors.lastname: Tauchi
authors.affiliation: Department of Paediatrics, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inukai
authors.affiliation: Department of Paediatrics, University of Yamanashi, Chuo, Yamanashi, Japan.
authors.forename: Kanji
authors.initials: K
authors.lastname: Sugita
authors.affiliation: Department of Paediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Ishii
authors.affiliation: Department of Paediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Eguchi
mesh_terms: D001374:Azacitidine / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism / Q000502:physiology; D019175:DNA Methylation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D019942:Genes, p16; D025743:HMGA2 Protein / Q000037:antagonists & inhibitors*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007223:Infant; D035683:MicroRNAs / Q000494:pharmacology* / Q000502:physiology; D058990:Molecular Targeted Therapy / Q000379:methods; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism / Q000502:physiology; D009429:Netropsin / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000628:therapy*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D035602:Transcriptional Elongation Factors; D015854:Up-Regulation
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D025743:HMGA2 Protein; C497422:KMT2A protein, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D035602:Transcriptional Elongation Factors; C487931:mirnlet7 microRNA, human; D051788:Myeloid-Lymphoid Leukemia Protein; C081449:AFF1 protein, human; D009429:Netropsin; D011495:Histone-Lysine N-Methyltransferase; D001374:Azacitidine
keywords: HMGA2; KMT2A; infant leukaemia; lymphoid malignancies