Lentivirus-mediated RNA interference targeting FAMLF-1 inhibits cell growth and enhances cell differentiation of acute myeloid leukemia partially differentiated cells via inhibition of AKT and c-MYC

// Yuan-Mao Huang 1, 2, 3 , Yi Zheng 1 , Jing-Gang Li 2 , Xue-Chun Wang 1 , Ze-Chuan Wang 1 , Wan-Ling Chen 1 , Li-Li Pan 2 , Yang Li 2 , Dong-Feng Luo 1 and Shao-Yuan Wang 1, 2 1 Union Clinical Medical College, Fujian Medical University, Fuzhou 350001, P.R. China 2 Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou 350001, P.R. China 3 Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou 363000, P.R. China Correspondence to: Shao-Yuan Wang, email: shaoyuanwang@mail.fjmu.edu.cn Keywords: acute myeloid leukemia partially differentiated (FAB-M2), FAMLF-1 gene, miR-181a1, single nucleotide polymorphism haplotype, pathogenesis Received: April 19, 2017      Accepted: September 03, 2017      Published: September 26, 2017 ABSTRACT Genetic heterogeneity is the basis of clinical heterogeneity among different subtypes of AML. We have successfully cloned a gene related to AML termed FAMLF from a FAB-M2 patient’s sample of a second largest AML pedigree. Then we revealed at least three splice variants, named as FAMLF-1 , FAMLF-2 and FAMLF-3 , and found miR181a1/b1 in the second intron of FAMLF gene family. Higher expression of FAMLF-1 was related to a higher complete remission (CR) rate, but shorter relapse free survival (RFS) in AML. We further found that the FAMLF-1 single nucleotide polymorphism (SNP) haplotype and its expression were positively correlated to clinical parameters of acute myeloid leukemia partially differentiated (FAB-M2) patients, but not FAB non-M2 patients or Acute Monocytic Leukemia (FAB-M5) patients. GTAGG SNP haplotype of FAMLF gene might increase FAB-M2 susceptibility in Han population and act as a useful candidate biomarker for FAB-M2 screening. We also demonstrated that FAMLF-1 gene silencing in FAB-M2 cells could lead to proliferation inhibition, cell cycle G0/G1 phase arrest, and differentiation promotion independent of its intronic miR-181a1, which might be related to Akt/c-Myc pathway. These findings reveal a role of FAMLF-1 as a potential pathogenic gene for FAB-M2.