Song Li, Lin Hai-Shuang, Gong Jia-Nan, Han Hua, Wang Xiao-Shuang, Su Rui, Chen Ming-Tai, Shen Chao, Ma Yan-Ni, Yu Jia, Zhang Jun-Wu
The State Key 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 100005, China.
Department of Obstetrics and Gynecology, Hebei General Hospital, Shijiazhuang 050051, China.
Oncotarget. 2017 Jul 18;8(33):55453-55466. doi: 10.18632/oncotarget.19325. eCollection 2017 Aug 15.
Myelopoiesis is under the control of a complex network containing various regulation factors. Deregulation of any important regulation factors may result in serious consequences including acute myeloid leukemia (AML). In order to find out the genes that may take a part in AML development, we analyzed data from AML cDNA microarray (GSE2191) in the NCBI data pool and noticed that heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is abnormally over-expressed in AML patients. Then we investigated the function and mechanisms of hnRNP A1 in myeloid development. A gradually decreased hnRNP A1 expression was detected during granulocytic differentiation in ATRA-induced-NB4 and HL-60 cells and cytokines-induced hematopoietic stem and progenitor cells. By function-loss and winning experiments we demonstrated hnRNP A1's inhibition role via inhibiting expression of C/EBPα, a key regulator of granulocytic differentiation, in the granulocytic differentiation. During granulocytic differentiation the decrease of hnRNP A1 reduces inhibition on C/EBPα expression, and the increased C/EBPα promotes the differentiation. We also demonstrated that miR-451 promotes granulocytic differentiation via targeting to and down-regulating hnRNP A1, and hnRNP A1 positively regulates c-Myc expression. Summarily, our results revealed new function and mechanisms of hnRNP A1 in normal granulocytiesis and the involvement of a feed-back loop comprising c-Myc, miR-451 and hnRNP A1 in AML development.
髓系造血受一个包含多种调控因子的复杂网络的控制。任何重要调控因子的失调都可能导致严重后果，包括急性髓系白血病（AML）。为了找出可能参与AML发生发展的基因，我们分析了NCBI数据库中AML cDNA微阵列（GSE2191）的数据，发现异质性细胞核核糖核蛋白A1（hnRNP A1）在AML患者中异常过度表达。然后我们研究了hnRNP A1在髓系发育中的功能和机制。在全反式维甲酸诱导的NB4和HL-60细胞以及细胞因子诱导的造血干细胞和祖细胞的粒细胞分化过程中，检测到hnRNP A1表达逐渐降低。通过功能缺失和获得实验，我们证明了hnRNP A1在粒细胞分化过程中通过抑制粒细胞分化的关键调节因子C/EBPα的表达发挥抑制作用。在粒细胞分化过程中，hnRNP A1的减少降低了对C/EBPα表达的抑制，而C/EBPα的增加促进了分化。我们还证明了miR-451通过靶向并下调hnRNP A1促进粒细胞分化，并且hnRNP A1正向调节c-Myc的表达。总之，我们的结果揭示了hnRNP A1在正常粒细胞生成中的新功能和机制，以及由c-Myc、miR-451和hnRNP A1组成的反馈环参与AML的发生发展。
