Upregulation of miR-99a is associated with poor prognosis of acute myeloid leukemia and promotes myeloid leukemia cell expansion

// Xiaohui Si 1 , Xiaoyun Zhang 1 , Xing Hao 1 , Yunan Li 1 , Zizhen Chen 1 , Yahui Ding 1 , Hui Shi 1 , Jie Bai 1 , Yingdai Gao 1, 2, 3 , Tao Cheng 1, 2, 3, 4 , Feng-Chun Yang 5, 6 , Yuan Zhou 1, 2, 3 1 State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China 2 Center for Stem Cell Medicine, Chinese Academy of Medical Sciences, Tianjin, China 3 Department of Stem Cell & Regenerative Medicine, Peking Union Medical College, Tianjin, China 4 Collaborative Innovation Center for Cancer Medicine, Tianjin, China 5 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA 6 Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA Correspondence to: Yuan Zhou, email: yuanzhou@ihcams.ac.cn Feng-Chun Yang, email: fxy37@med.miami.edu Keywords: leukemia stem cell, microRNA, acute myeloid leukemia, miR-99a Received: July 29, 2016 Accepted: October 14, 2016 Published: October 27, 2016 ABSTRACT Leukemia stem cells (LSCs) can resist available treatments that results in disease progression and/or relapse. To dissect the microRNA (miRNA) expression signature of relapse in acute myeloid leukemia (AML), miRNA array analysis was performed using enriched LSCs from paired bone marrow samples of an AML patient at different disease stages. We identified that miR-99a was significantly upregulated in the LSCs obtained at relapse compared to the LSCs collected at the time of initial diagnosis. We also found that miR-99a was upregulated in LSCs compared to non-LSCs in a larger cohort of AML patients, and higher expression levels of miR-99a were significantly correlated with worse overall survival and event-free survival in these AML patients. Ectopic expression of miR-99a led to increased colony forming ability and expansion in myeloid leukemia cells after exposure to chemotherapeutic drugs in vitro and in vivo , partially due to overcoming of chemotherapeutic agent-mediated cell cycle arrest. Gene profiling and bioinformatic analyses indicated that ectopic expression of miR-99a significantly upregulated genes that are critical for LSC maintenance, cell cycle, and downstream targets of E2F and MYC. This study suggests that miR-99a has a novel role and potential use as a biomarker in myeloid leukemia progression.