Dissection of the Major Hematopoietic Quantitative Trait Locus in Chromosome 6q23.3 Identifies miR-3662 as a Player in Hematopoiesis and Acute Myeloid Leukemia.

Autor:	Maharry SE; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Walker CJ; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Liyanarachchi S; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Mehta S; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Patel M; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Bainazar MA; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Huang X; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Lankenau MA; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Hoag KW; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Ranganathan P; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Garzon R; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Blachly JS; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Guttridge DC; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Bloomfield CD; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., de la Chapelle A; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio., Eisfeld AK; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio. ann-kathrin.eisfeld@osumc.edu.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2016 Sep; Vol. 6 (9), pp. 1036-51. Date of Electronic Publication: 2016 Jun 27.
DOI:	10.1158/2159-8290.CD-16-0023
Abstrakt:	Unlabelled: 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. Significance: 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. (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
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