title: Dissection of the Major Hematopoietic Quantitative Trait Locus in Chromosome 6q23.3 Identifies miR-3662 as a Player in Hematopoiesis and Acute Myeloid Leukemia.
abstract: Chromosomal aberrations and multiple genome-wide association studies (GWAS) have established a major hematopoietic quantitative trait locus in chromosome 6q23.3. The locus comprises an active enhancer region, in which some of the associated SNPs alter transcription factor binding. We now identify miR-3662 as a new functional driver contributing to the associated phenotypes. The GWAS SNPs are strongly associated with higher miR-3662 expression. Genome editing of rs66650371, a three-base-pair deletion, suggests a functional link between the SNP genotype and the abundance of miR-3662. Increasing miR-3662's abundance increases colony formation in hematopoietic progenitor cells, particularly the erythroid lineage. In contrast, miR-3662 is not expressed in acute myeloid leukemia cells, and its overexpression has potent antileukemic effects in vitro and in vivo Mechanistically, miR-3662 directly targets NF-κB-mediated transcription. Thus, miR-3662 is a new player of the hematopoietic 6q23.3 locus.
  
  
  
  The characterization of miR-3662 has identified a new actor in the prominent hematopoietic quantitative trait locus in chromosome 6q23.3. The mechanistic insights into miR-3662's function may reveal novel or only partially known pathways for normal and malignant hematopoietic cell proliferation. Cancer Discov; 6(9); 1036-51. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Sophia E
authors.initials: SE
authors.lastname: Maharry
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Walker
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Sandya
authors.initials: S
authors.lastname: Liyanarachchi
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Sujay
authors.initials: S
authors.lastname: Mehta
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Mitra
authors.initials: M
authors.lastname: Patel
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Maryam A
authors.initials: MA
authors.lastname: Bainazar
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Huang
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Malori A
authors.initials: MA
authors.lastname: Lankenau
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Hoag
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Parvathi
authors.initials: P
authors.lastname: Ranganathan
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Ramiro
authors.initials: R
authors.lastname: Garzon
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: James S
authors.initials: JS
authors.lastname: Blachly
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Denis C
authors.initials: DC
authors.lastname: Guttridge
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Clara D
authors.initials: CD
authors.lastname: Bloomfield
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio. ann-kathrin.eisfeld@osumc.edu.
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Eisfeld
mesh_terms: D000483:Alleles; D000818:Animals; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002896:Chromosomes, Human, Pair 6; D003114:Colony-Forming Units Assay; D004195:Disease Models, Animal; D005260:Female; D050982:GATA1 Transcription Factor / Q000378:metabolism; D018628:Gene Dosage; D015973:Gene Expression Regulation, Leukemic; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D040641:Quantitative Trait Loci; D034622:RNA Interference; D020218:Response Elements; D015398:Signal Transduction
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D050982:GATA1 Transcription Factor; C000603399:MIRN-3662 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D051550:I-kappa B Kinase