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

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

Nature communications (2021-10-24)
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, Ya-Huei Kuo
PMID34686664
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.

MATERIALS
Product Number
Brand
Product Description
IP05
Millipore
Protein G Plus/Protein A Agarose Suspension, Protein G PLUS/Protein A-Agarose mixture specifically formulated for immunoprecipitation.