MiR-181 family: regulators of myeloid differentiation and acute myeloid leukemia as well as potential therapeutic targets.

Su, R; Lin, H-S; Zhang, X-H; Yin, X-L; Ning, H-M; Liu, B; Zhai, P-F; Gong, J-N; Shen, C; Song, L; Chen, J; Wang, F; Zhao, H-L; Ma, Y-N; Yu, J; Zhang, J-W

Su, R; Lin, H-S; Zhang, X-H; Yin, X-L; Ning, H-M; Liu, B; Zhai, P-F; Gong, J-N; Shen, C; Song, L; Chen, J; Wang, F; Zhao, H-L; Ma, Y-N; Yu, J; Zhang, J-W.

Afiliación

Su R; Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Lin HS; Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Zhang XH; Department of Hematology, the 303 Hospital, Nanning, Guangxi, China.
Yin XL; Department of Hematology, the 303 Hospital, Nanning, Guangxi, China.
Ning HM; Institute of Military Hemopoietic Stem Cell, Department of Stem Cell Transplantation Center, Hospital Affiliated to Academy of Military Medical Science, Beijing, China.
Liu B; 307-lvy Translational Medicine Center, Laboratory of Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China.
Zhai PF; Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Gong JN; Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Shen C; Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Song L; Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Chen J; Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Wang F; Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Zhao HL; Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Ma YN; Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Yu J; Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Zhang JW; Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Oncogene ; 34(25): 3226-39, 2015 Jun.

Article en En | MEDLINE | ID: mdl-25174404

RESUMEN

MicroRNAs have been shown to play an important role in normal hematopoisis and leukemogenesis. Here, we report function and mechanisms of miR-181 family in myeloid differentiation and acute myeloid leukemia (AML). The aberrant overexpression of all the miR-181 family members (miR-181a/b/c/d) was detected in French-American-British M1, M2 and M3 subtypes of adult AML patients. By conducting gain- and loss-of-function experiments, we demonstrated that miR-181a inhibits granulocytic and macrophage-like differentiation of HL-60 cells and CD34+ hematopoietic stem/progenitor cells (HSPCs) by directly targeting and downregulating the expression of PRKCD (which then affected the PRKCD-P38-C/EBPα pathway), CTDSPL (which then affected the phosphorylation of retinoblastoma protein) and CAMKK1. The three genes were also demonstrated to be the targets of miR-181b, miR-181c and miR-181d, respectively. Significantly decreases in the expression levels of the target proteins were detected in AML patients. Inhibition of the expression of miR-181 family members owing to Lenti-miRZip-181a infection in bone marrow blasts of AML patients increased target protein expression levels and partially reversed myeloid differentiation blockage. In the mice implanted with AML CD34+ HSPCs, expression inhibition of the miR-181 family by Lenti-miRZip-181a injection improved myeloid differentiation, inhibited engraftment and infiltration of the leukemic CD34+ cells into the bone marrow and spleen, and released leukemic symptoms. In conclusion, our findings revealed new mechanism of miR-181 family in normal hematopoiesis and AML development, and suggested that expression inhibition of the miR-181 family could provide a new strategy for AML therapy.

Asunto(s)

Diferenciación Celular; Leucemia Mieloide Aguda/genética; Leucemia Mieloide Aguda/patología; MicroARNs/genética; Terapia Molecular Dirigida; Células Mieloides/patología; Animales; Secuencia de Bases; Proteínas Potenciadoras de Unión a CCAAT/metabolismo; Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/genética; Bovinos; Diferenciación Celular/efectos de los fármacos; Regulación Neoplásica de la Expresión Génica/efectos de los fármacos; Granulocitos/efectos de los fármacos; Granulocitos/patología; Células HL-60; Células Madre Hematopoyéticas/patología; Humanos; Leucemia Mieloide Aguda/tratamiento farmacológico; Leucemia Mieloide Aguda/metabolismo; Macrófagos/efectos de los fármacos; Macrófagos/patología; Ratones; Células Mieloides/efectos de los fármacos; Proteína Quinasa C-delta/genética; ARN Mensajero/genética; ARN Mensajero/metabolismo; Ratas; Transducción de Señal/efectos de los fármacos; Acetato de Tetradecanoilforbol/farmacología; Transducción Genética; Tretinoina/farmacología; Proteínas Supresoras de Tumor/genética

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Diferenciación Celular / Células Mieloides / MicroARNs / Terapia Molecular Dirigida Límite: Animals / Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2015 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google