Targeting dysfunction of microRNA in MLL leukemia

In our latest manuscript in Leukemia, we describe a putative additional mechanism for MYC deregulation downstream of MLL. We further demonstrate that IRAK1/4 inhibitor might improve the efficacy of BET inhibitor through synergistically downregulating MYC in MLL leukemias.

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How it started?

 Polycomb (PcG) and Trithorax (TrxG) group proteins are evolutionarily conserved chromatin-modifying factors that maintains repressed or active gene expression states during development. The Mixed-Lineage Leukemia (MLL) protein is the founding member of human TrxG proteins, and its disruption characteristically associates with a subset of aggressive acute leukemias. Neverhteless, current well accepted model of the function of MLL is limited to that mature MLL serves as an epigenetic regulator in the form of an intramolecular complex.

 Prof. Han Liu’s group is dedicated to uncover the biological function of MLL and the mechanism underlying MLL leukemogenesis. When I joined his group in Sep 2014 as a Ph.D. candidate, I started working on the novel function of MLL protein played in the cytoplasm, which led to a publication in Cell Discovery [1]. In that paper, we first demonstrated that the MLLC180 subunit alone can localize in cytoplasm processing bodies (P-bodies), where miRNA-mediated gene silencing takes place. Furthermore, we found that MLL is required for the miRNA-mediated translational repression. This study lead to the hereby described project which aimed at better understanding the potential functional link between miRNA dysfunction and MLL-rearranged leukemia.

 Hypothesis and challenges

 Multiple miRNAs have been found to be dysregulated in MLL leukemias. However, since only a small fraction of miRNAs are functional, it is not clear whether the expression levels of miRNAs reflect their actual contribution to the pathogenesis of MLL leukemia. Considering that the abundance of wild-type MLL protein was reduced in MLL leukemic cells, we reasoned that the function of a subset of miRNAs would be compromised and may play a critical role in the pathogenesis of MLL leukemia. Our ultimate goal is to provide a rational foundation for the treatment of MLL leukemias.

 

 Main results

 We believe our study provides key and original findings in the field of MLL leukemia. For the first time, we demonstrated that:

 1. The miRNA-mediated gene silencing was impaired due to the downregulation of wild-type MLL, especially the MLLC180 subunit.

2.  The expression of MYC proteins could escape translational repression by let-7a in MLL leukemic cells.

3.  IRAK1/4 inhibition can improve the efficacy of BET inhibitors in MLL leukemias by restoring the protein level of MLL and the MYC-suppressing function of let-7a.

 

 Further research

 The present work is only the beginning of our endeavor in better understanding the role of MLL played in the miRNA-mediated translational repression. Our next step is to clarify the detailed mechanisms underlying MLL regulated miRNA dysfunction. Further studies are also clearly needed to investigate the pre-clinical usefulness of the combination therapy with IRAK1/4 and BET inhibitors. It would be interesting to determine whether BET and IRAK1/4 inhibitors could be extended to therapeutically combined target other types of cancers known to harbor MYC overexpression.

 

This project was really a dream come true. As with all the great experiences, it’s the people we were involved, directly and indirectly that made this story so amazing:

 Prof. Han Liu, I was very fortunate to meet with him during my Ph.D. training, who made all the aspects of this project possible, the daily laboratory meeting and journal club discussions greatly advanced the progression of this project, the co-authors of this manuscript (Xiaoyan Cheng, Ruiheng Wang, Yuting Tan, Yan Sun, Maolin Ge, Dan Li, Xiongyu Xu), all the fantastic members of the Liu lab who provided me with invaluable suggestions (Ting Kang, Zhihong Chen, Shifen Wang, Shufeng Xie, Wenbin Wang and Hongyu Liang). I will never forget the times we together had spent in the past five years. And many others not mentioned in the above at the Shanghai Institute of Hematology. Finally, I would like to thank my wife Dan Jiang for the support and encouragement during this project.

 

Written by Shouhai Zhu [a, b].

 [a] State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.

[b] Current address: Department of Oncology, Mayo Clinic.

 

 References

 [1] Zhu SH, Chen ZH, Wang RH, Tan YT, Ge ML, Sun Y, et al. MLL is required for miRNA-mediated translational repression. Cell Discov. 2019; 5:43.

Go to the profile of Han Liu

Han Liu

Professor, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University

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