Abstract

Acute myeloid leukemia (AML) harboring inv(16)(p13q22) expresses high levels of miR-126. Here we show that the CBFB-MYH11 (CM) fusion gene upregulates miR-126 expression through aberrant miR-126 transcription and perturbed miR-126 biogenesis via the HDAC8/RAN-XPO5-RCC1 axis. Aberrant miR-126 upregulation promotes survival of leukemia-initiating progenitors and is critical for initiating and maintaining CM-driven AML. We show that miR-126 enhances MYC activity through the SPRED1/PLK2-ERK-MYC axis. Notably, genetic deletion of miR-126 significantly reduces AML rate and extends survival in CM knock-in mice. Therapeutic depletion of miR-126 with an anti-miR-126 (miRisten) inhibits AML cell survival, reduces leukemia burden and leukemia stem cell (LSC) activity in inv(16) AML murine and xenograft models. The combination of miRisten with chemotherapy further enhances the anti-leukemia and anti-LSC activity. Overall, this study provides molecular insights for the mechanism and impact of miR-126 dysregulation in leukemogenesis and highlights the potential of miR-126 depletion as a therapeutic approach for inv(16) AML.

miR-126 is highly expressed in inv(16) Acute myeloid leukemia (AML) but its role is unclear. Here, the authors show that the aberrant expression of miR-126 in inv(16) AML is directly due to the CBFB-MYH11 fusion gene and that it can promote AML development and leukemia stem cell maintenance, highlighting miR-126 as a therapeutic target for inv(16) AML patients

Details

Title
Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance
Author
Zhang, Lianjun 1 ; Nguyen Le Xuan Truong 1 ; Chen, Ying-Chieh 1 ; Wu Dijiong 2   VIAFID ORCID Logo  ; Cook, Guerry J 1 ; Hoang Dinh Hoa 1 ; Brewer, Casey J 1 ; He, Xin 1 ; Dong Haojie 1 ; Li, Shu 3 ; Li, Man 1 ; Zhao, Dandan 1 ; Qi Jing 1 ; Wei-Kai, Hua 1 ; Cai Qi 1 ; Carnahan, Emily 1 ; Chen, Wei 4 ; Wu Xiwei 4 ; Swiderski Piotr 5 ; Rockne Russell C 6   VIAFID ORCID Logo  ; Kortylewski Marcin 7   VIAFID ORCID Logo  ; Li, Ling 1 ; Zhang, Bin 1   VIAFID ORCID Logo  ; Marcucci Guido 1   VIAFID ORCID Logo  ; Kuo Ya-Huei 1   VIAFID ORCID Logo 

1  City of Hope Medical Center, Gehr Family Center for Leukemia Research, Department of Hematological Malignancies Translational Science, Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, Duarte, USA (GRID:grid.410425.6) (ISNI:0000 0004 0421 8357) 
2  First Affiliated Hospital of Zhejiang Chinese Medical University, Department of Hematology, Hangzhou, China (GRID:grid.417400.6) (ISNI:0000 0004 1799 0055) 
3  Zhejiang University School of Medicine, Department of Hematology, The Second Affiliated Hospital, Hangzhou, China (GRID:grid.13402.34) (ISNI:0000 0004 1759 700X) 
4  City of Hope Medical Center, Integrated Genomics Core, Beckman Research Institute, Duarte, USA (GRID:grid.410425.6) (ISNI:0000 0004 0421 8357) 
5  City of Hope Medical Center, Department of Molecular Medicine, Beckman Research Institute, Duarte, USA (GRID:grid.410425.6) (ISNI:0000 0004 0421 8357) 
6  City of Hope Medical Center, Department of Computational and Quantitative Medicine, Division of Mathematical Oncology, Beckman Research Institute, Duarte, USA (GRID:grid.410425.6) (ISNI:0000 0004 0421 8357) 
7  City of Hope Medical Center, Department of Immuno-oncology, Beckman Research Institute, Duarte, USA (GRID:grid.410425.6) (ISNI:0000 0004 0421 8357) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-021-26420-7
ProQuest document ID
2584639589
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.