title: miR-125b regulates differentiation and metabolic reprogramming of T cell acute lymphoblastic leukemia by directly targeting A20.
abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy. Although it has been reported that overexpression of miR-125b leads to T-ALL development, the underlying mechanisms of miR-125b action are still unclear. The goal of this study is to delineate the role of miR-125b in T-ALL development. We found that miR-125b is highly expressed in undifferentiated leukemic T cells (CD4-negative) while its expression is low in differentiated T cells (CD4-positive). Overexpression of miR-125b increased the CD4-negative population in T cells, whereas depletion of miR-125b by miR-125b-sponge decreased the CD4-negative cell population. We identified that A20 (TNFAIP3) is a direct target of miR-125b in T cells. Overexpression of miR-125b also increased glucose uptake and oxygen consumption in T cells through targeting A20. Furthermore, restoration of A20 in miR-125b-overexpressing cells decreased the CD4-negative population in T cell leukemia, and decreased glucose uptake and oxygen consumption to the basal level of T cells transfected with vector. In conclusion, our data demonstrate that miR-125b regulates differentiation and reprogramming of T cell glucose metabolism via targeting A20. Since both de-differentiation and dysregulated glucose metabolism contribute to the development of T-cell leukemia, these findings provide novel insights into the understanding and treatment of T-ALL.
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
authors.forename: Zixing
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Smith
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Hung T
authors.initials: HT
authors.lastname: Khong
authors.affiliation: School of Computing, University of South Alabama, Mobile, AL, USA.
authors.forename: Jingshan
authors.initials: J
authors.lastname: Huang
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
authors.forename: Eun-Young Erin
authors.initials: EE
authors.lastname: Ahn
authors.affiliation: Cancer Research Institute, Central South University, Changsha, Hunan, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.|Department of Biochemistry & Molecular Biology, University of South Alabama, Mobile, AL, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Tan
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D065150:Cellular Reprogramming; D004734:Energy Metabolism; D015973:Gene Expression Regulation, Leukemic; D005947:Glucose / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014162:Transfection; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: C531888:MIRN125 microRNA, human; D035683:MicroRNAs; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D005947:Glucose
keywords: A20; T cell; differentiation; lymphocytic leukemia; miR-125b