The miR-17 approximately 92 cluster contributes to MLL leukemia through the repression of MEIS1 competitor PKNOX1 Journal Article

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Authors: Mian, Y. A.; Zeleznik-Le, N. J.
Article Title: The miR-17 approximately 92 cluster contributes to MLL leukemia through the repression of MEIS1 competitor PKNOX1
Abstract: Mixed lineage leukemias have a relatively poor prognosis and arise as a result of translocations between the MLL(KMT2A) gene and one of multiple partner genes. Downstream targets of MLL are aberrantly upregulated and include the developmentally important HOX genes and MEIS1, as well as multiple microRNAs (miRNAs), including the miR-17 approximately 92 cluster. Here we examined the contribution of specific miRNAs to MLL leukemias through knockdown studies utilizing custom anti-microRNA oligonucleotides. Combinatorial treatment against miR-17-5p and miR-19a-3p of the miR-17 approximately 92 cluster dramatically reduces colony forming ability of MLL-fusion containing cell lines relative to non-MLL acute myeloid leukemia (AML) controls. To determine the mechanism by which these miRNAs contribute to leukemia, we validated PKNOX1 as a target of both miR-17-5p and miR-19a-3p. MEIS1 and PKNOX1 are TALE domain proteins that participate in ternary complexes with HOX and PBX partners. Here we establish the competitive relationship between PKNOX1 and MEIS1 in PBX-containing complex formation and determine the antagonistic role of PKNOX1 to leukemia in a murine MLL-AF9 model. These data implicate the miR-17 approximately 92 cluster as part of a regulatory mechanism necessary to maintain MEIS1/HOXA9 -mediated transformation in MLL leukemia, indicating that targeting multiple non-homologous miRNAs may be utilized as a novel therapeutic regimen.
Journal Title: Leukemia research
Volume: 46
ISSN: 1873-5835; 0145-2126
Publisher: Elsevier Inc  
Journal Place: England
Date Published: 2016
Start Page: 51
End Page: 60
Language: eng
DOI/URL:

10.1016/j.leukres.2016.04.006
Notes: LR: 20160609; CI: Copyright (c) 2016; GR: R01 HL087188/HL/NHLBI NIH HHS/United States; JID: 7706787; NIHMS781793; OID: NLM: NIHMS781793 [Available on 07/01/17]; OID: NLM: PMC4899285 [Available on 07/01/17]; OTO: NOTNLM; PMCR: 2017/07/01 00:00; 2016/02/05 [received]; 2016/04/06 [revised]; 2016/04/07 [accepted]; 2016/04/16 [aheadofprint]; ppublish