Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance

Lianjun Zhang, Le Xuan Truong Nguyen, Ying-Chieh Chen, Dijiong Wu, Guerry J. Cook, Dinh Hoa Hoang, Casey J. Brewer, Xin He, Haojie Dong, Shu Li, Man Li, Dandan Zhao, Jing Qi, Wei-Kai Hua, Qi Cai, Emily Carnahan, Wei Chen, Xiwei Wu, Piotr Swiderski, Russell C. Rockne, Marcin Kortylewski, Ling Li, Bin Zhang, Guido Marcucci and Ya-Huei Kuo ()
Additional contact information
Lianjun Zhang: City of Hope Medical Center
Le Xuan Truong Nguyen: City of Hope Medical Center
Ying-Chieh Chen: City of Hope Medical Center
Dijiong Wu: First Affiliated Hospital of Zhejiang Chinese Medical University
Guerry J. Cook: City of Hope Medical Center
Dinh Hoa Hoang: City of Hope Medical Center
Casey J. Brewer: City of Hope Medical Center
Xin He: City of Hope Medical Center
Haojie Dong: City of Hope Medical Center
Shu Li: Zhejiang University School of Medicine
Man Li: City of Hope Medical Center
Dandan Zhao: City of Hope Medical Center
Jing Qi: City of Hope Medical Center
Wei-Kai Hua: City of Hope Medical Center
Qi Cai: City of Hope Medical Center
Emily Carnahan: City of Hope Medical Center
Wei Chen: City of Hope Medical Center
Xiwei Wu: City of Hope Medical Center
Piotr Swiderski: City of Hope Medical Center
Russell C. Rockne: City of Hope Medical Center
Marcin Kortylewski: City of Hope Medical Center
Ling Li: City of Hope Medical Center
Bin Zhang: City of Hope Medical Center
Guido Marcucci: City of Hope Medical Center
Ya-Huei Kuo: City of Hope Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26420-7

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