title: MiR-100 regulates cell differentiation and survival by targeting RBSP3, a phosphatase-like tumor suppressor in acute myeloid leukemia.
abstract: Acute myeloblastic leukemia (AML) is characterized by the accumulation of abnormal myeloblasts (mainly granulocyte or monocyte precursors) in the bone marrow and blood. Though great progress has been made for improvement in clinical treatment during the past decades, only minority with AML achieve long-term survival. Therefore, further understanding mechanisms of leukemogenesis and exploring novel therapeutic strategies are still crucial for improving disease outcome. MicroRNA-100 (miR-100), a small non-coding RNA molecule, has been reported as a frequent event aberrantly expressed in patients with AML; however, the molecular basis for this phenotype and the statuses of its downstream targets have not yet been elucidated. In the present study, we found that the expression level of miR-100 in vivo was related to the stage of the maturation block underlying the subtypes of myeloid leukemia. In vitro experiments further demonstrated that miR-100 was required to promote the cell proliferation of promyelocytic blasts and arrest them differentiated to granulocyte/monocyte lineages. Significantly, we identified RBSP3, a phosphatase-like tumor suppressor, as a bona fide target of miR-100 and validated that RBSP3 was involved in cell differentiation and survival in AML. Moreover, we revealed a new pathway that miR-100 regulates G1/S transition and S-phase entry and blocks the terminal differentiation by targeting RBSP3, which partly in turn modulates the cell cycle effectors pRB/E2F1 in AML. These events promoted cell proliferation and blocked granulocyte/monocyte differentiation. Our data highlight an important role of miR-100 in the molecular etiology of AML, and implicate the potential application of miR-100 in cancer therapy.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou, China.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Zheng
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: X-J
authors.initials: XJ
authors.lastname: Zhang
authors.forename: D-D
authors.initials: DD
authors.lastname: Feng
authors.forename: X-Q
authors.initials: XQ
authors.lastname: Luo
authors.forename: C-W
authors.initials: CW
authors.lastname: Zeng
authors.forename: K-Y
authors.initials: KY
authors.lastname: Lin
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.forename: L-H
authors.initials: LH
authors.lastname: Qu
authors.forename: P
authors.initials: P
authors.lastname: Zhang
authors.forename: Y-Q
authors.initials: YQ
authors.lastname: Chen
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002470:Cell Survival; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000032:analysis / Q000502:physiology*; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology
chemical_list: C486483:CTDSPL protein, human; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C544266:MIRN100 microRNA, human; D035683:MicroRNAs; D016160:Retinoblastoma Protein; D025521:Tumor Suppressor Proteins