Targeting RBPMS selectively eliminates FOXO1-mediated stem cell signatures in mouse models of acute myeloid leukemia.
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Liu Ping, Zhang Sulin, Chen Bing-Yi, Chang Binhe, Jiang Yilun, Li Xiya, Chen Xinchi, Li Zi-Juan, Yang Ruirui, Wang Xiaoning, Xu Chun-Hui, Liu Xiaomeng, Liu Na, Jia Yuanyuan, Yu Peng-Cheng, Wang Yong, Zong Li-Juan, Hu Cheng-Long, Hou Hui, Cao Duanhua, Li Xutong, Deng Chu-Han, Ren Yi-Yi, Zhao Mu-Ying, Ma Xinyi, Cui Rongrong, Teng Dan, Chen Miao, Wang Roujia, Jin Jiacheng, Jiang Shi-Yu, Yan Xiaojing, Xue Kai, Zhang Qunling, Li Jianfeng, Dai Enyong, Shen Shuhong, Wang Zhikai, Ye Xueshi, Zhang Jin, Liu Yu, Cui Wenguo, Lu Min, Zhao Wei-Li, Chang Chun-Kang, He Peng-Cheng, Chen Zhu, Chen Sai-Juan, Zheng Mingyue, Sun Xiao-Jian, Wang Lan
Аннотация
Leukemia is a malignant tumor with a high recurrence rate and poor prognosis for patients. Thus, there is an urgent need to explore new therapeutic targets that play critical roles in leukemogenesis but have little effect on normal hematopoietic cells. Here, we show that RNA binding protein with multiple splicing (RBPMS), which is highly expressed in acute myeloid leukemia (AML) and associated with poor prognosis of AML, plays critical roles in leukemogenesis. Our study shows that inhibition of RBPMS inhibits self-renewal of leukemia-initiating cells (LICs) and leukemia development but has little effect on normal hematopoiesis. Mechanistically, RBPMS recruits the N6-methyladenosine (m6A) reader insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), which promotes the stability of the forkhead box O1 (FOXO1) mRNA in an m6A-dependent manner. Moreover, RBPMS contributes to the progression of leukemia by directly binding to FOXO1 and promoting FOXO1-regulated glycolysis. Overexpression of FOXO1 has been shown to reverse RBPMS inhibition-induced phenotypes in both leukemic cells and mouse models. We also designed a specific inhibitor of RBPMS that has therapeutic effects in AML patient-derived xenograft (PDX) models. We therefore highlight RBPMS as a promising drug target for leukemia therapy.