IntroductionAcute myeloid leukemia (AML) is a heterogeneous group of blood cancers characterized by increased, uncontrolled proliferation of hematopoietic progenitors, and a blockage in myeloid differentiation is the major characteristic of AML. 1 According to the French-American-British classification system, AMLs involving the monocytic and granulocytic lineage account for 85% (M1 to M5 subtypes) of adult patients. 2 Under normal conditions, monocytes and granulocytes develop from long-term hematopoietic stem cells (LT-HSCs) in BM under the influence of a complex network of cytokins such as G-CSF, GM-CSF, and M-CSF, and transcription factors such as PU.1, C/EBP, IFN consensus sequence binding protein/IFN regulatory factor 8, Krüppel-like factor 4, c-Maf, and C/EBP⑀. [3][4][5][6] MicroRNAs (miRNAs) that negatively regulate gene expression at posttranscriptional level 7 have also been identified as crucial regulators in normal and malignant myeloid differentiation. Expression and function analyses have unraveled their important regulatory roles during hematopoiesis. 8 In a previous study, we demonstrated a significantly decreased expression of miR-29a and 142-3p in the peripheral blood mononuclear cells (PBMNCs) from AML patients (French-AmericanBritish M1 to M5 subtypes). 9 These 2 miRNAs were also reported to be down-regulated in a variety of tumors and to act as tumor suppressors. [10][11][12] The miR-29a cluster is one of the most studied miRNA clusters. Down-regulation of miR-29a was observed in AML samples with deletions of 7q (del7q). 10 Several genes have been reported to be silenced by miR-29, most of which are potential oncogenes, such as SKI, Tcl1, the p53 upstream inhibitors p85a and CDC42, and the Bcl2 family members Bcl2 and Mcl1. 11 Meanwhile, miR-142-3p, first identified as being uniquely expressed in hematopoietic system, is aberrantly expressed in T-cell and B-cell leukemia. 12 In addition, increased miR-142-3p expression has been observed at different stages of normal granulocytopoiesis. 13 Validated targets of miR-142-3p include ADCY9, 14 CD133, 16 and the RAC1. 17 In this study, we sought to investigate role of these 2 miRNAs in monocytic and granulocytic differentiation (also called myeloid differentiation), and to test whether their down-regulation is related to the differentiation block in AML blasts. Using the leukemia cell lines, NB4, HL-60, and THP-1 18-23 we observed up-regulation of miR-29a and miR-142-3p expression during all-trans-retinoic acid (ATRA)-induced granulocytic differentiation and phorbol 12-myristate 13-acetate (PMA)-induced monocytic differentiation, and examined effects of overexpression or knockdown of each miRNA on myeloid differentiations. Moreover, we identified targets of both miRNAs and examined direct effect of the target genes on myeloid differentiation. Similar results were also obtained in myeloid induction cultures of CD34 ϩ hematopoietic stem/ progenitor cells (HSPCs) derived from normal human umbilical cord blood (UCB) and BM from healthy donors and AML p...

The present study explored the association of long non-coding RNA (lncRNA) antisense non-coding RNA in the INK4 locus (ANRIL) with the development of acute myeloid leukemia (AML) clinical features and prognosis of patients with AML. Bone marrow mononuclear cells (BMMCs) were obtained from 178 patients with de novo AML prior to initial therapy and from 30 healthy donors. The expression of lncRNA ANRIL in BMMCs was detected by reverse transcription-quantitative PCR. Complete remission (CR) was assessed after induction therapy. Event-free survival (EFS) and overall survival (OS) were evaluated during the follow-up. The levels of lncRNA ANRIL were increased in patients with AML compared with those in healthy donors and were capable of distinguishing patients with AML from healthy donors (area under the curve, 0.886; 95% CI, 0.820-0.952). Furthermore, lncRNA ANRIL was associated with an increased occurrence internal tandem duplications in the FMS-like tyrosine kinase 3, decreased occurrence inv(16) or t(16;6), intermediate-risk and poor-risk stratification while no association of lncRNA ANRIL was identified with French-American-British classification, cytogenetics, isolated biallelic CCAAT/enhancer-binding protein α mutation and nucleophosmin 1 mutation in patients with AML. Furthermore, lncRNA ANRIL was significantly associated with a lower CR rate. In addition, EFS and OS were shorter in patients with high expression of lncRNA ANRIL compared with those in patients with low expression of lncRNA ANRIL. Multivariate Cox regression analyses revealed that high expression of lncRNA ANRIL, poor-risk stratification and white blood cells (>10.0x10 9 cells/l) were independent prognostic factors for shorter EFS, while high expression of lncRNA ANRIL and poorer risk stratification were independent prognostic factors for shorter OS. The present results suggested that lncRNA ANRIL has clinical relevance as a biomarker for assisting diagnosis treatment decisions and prognosis prediction and the identification of potential drug target for AML.