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CircMYBL2, a circRNA from MYBL2, Regulates FLT3 Translation by Recruiting PTBP1 to Promote FLT3-ITD AML Progression

Yu-Meng Sun, Wen-Tao Wang, Zhan-Cheng Zeng, Tian-Qi Chen, Cai Han, Qi Pan, Wei Huang, Ke Fang, Lin-Yu Sun, Yan-Fei Zhou, Xue-Qun Luo, Chengwei Luo, Xin Du and Yue-Qin Chen

Key Points

  • We discovered a circRNA, circMYBL2, that regulates FLT3 translation by recruiting PTBP1 to promote FLT3-ITD AML progression.

  • Targeting circMYBL2 specifically inhibits the proliferation and promotes differentiation of FLT3-ITD AML cells in vitro and in vivo.

Abstract

Internal tandem duplication (ITD) mutations within the FMS-like tyrosine kinase-3 (FLT3) occur in up to 30% of acute myeloid leukemia (AML) patients and confer a very poor prognosis. The oncogenic form of FLT3 is an important therapeutic target, and inhibitors specifically targeting FLT3 kinase can induce complete remission; however, relapse after remission has been observed due to acquired resistance with secondary mutations in FLT3, highlighting the need for new strategies to target FLT3-ITD mutations. Recent studies have reported that the aberrant formations of circular RNAs (circRNAs) are biological tumorigenesis-relevant mechanisms and potential therapeutic targets. Herein, we discovered a circRNA, circMYBL2, derived from the cell cycle checkpoint gene MYBL2. CircMYBL2 is more highly expressed in AML patients with FLT3-ITD mutations than in those without the FLT3-ITD mutation. We found that circMYBL2 knockdown specifically inhibits proliferation and promotes the differentiation of FLT3-ITD AML cells in vitro and in vivo. Interestingly, we found that circMYBL2 significantly influences the protein level of mutant FLT3 kinase, which contributes to the activation of FLT3-ITD-dependent signaling pathways. Mechanistically, circMYBL2 enhanced the translational efficiency of FLT3 kinase by increasing the binding of PTBP1 to FLT3 mRNA. Moreover, circMYBL2 knockdown impaired the cytoactivity of inhibitor-resistant FLT3-ITD-positive cells, with a significant decrease in FLT3 kinase expression, followed by the inactivation of its downstream pathways. In summary, we are the first to reveal a circRNA that specifically influences FLT3-ITD AML and regulates FLT3 kinase levels through translational regulation, suggesting that circMYBL2 may be a potential therapeutic target for FLT3-ITD AML.

  • Submitted March 26, 2019.
  • Revision received August 6, 2019.
  • Accepted August 3, 2019.