Long non-coding RNA HOXB-AS3 promotes myeloid cell proliferation and its higher expression is an adverse prognostic marker in patients with acute myeloid leukemia and myelodysplastic syndrome
Huai-Hsuan Huang,
Fei-Yun Chen,
Wen-Chien Chou,
Hsin-An Hou,
Bor-Sheng Ko,
Chien-Ting Lin,
Jih-Luh Tang,
Chi-Cheng Li,
Ming Yao,
Woei Tsay,
Szu-Chun Hsu,
Shang-Ju Wu,
Chien-Yuan Chen,
Shang-Yi Huang,
Mei-Hsuan Tseng,
Hwei-Fang Tien,
Ruey-Hwa Chen
Affiliations
Huai-Hsuan Huang
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital
Fei-Yun Chen
Institute of Biological Chemistry, Academia Sinica
Wen-Chien Chou
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital
Hsin-An Hou
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital
Bor-Sheng Ko
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital
Chien-Ting Lin
Taicheng Stem Cell Therapy Center, National Taiwan University
Jih-Luh Tang
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital
Chi-Cheng Li
Taicheng Stem Cell Therapy Center, National Taiwan University
Ming Yao
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital
Woei Tsay
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital
Szu-Chun Hsu
Department of Laboratory Medicine, National Taiwan University Hospital, National Taiwan University
Shang-Ju Wu
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital
Chien-Yuan Chen
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital
Shang-Yi Huang
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital
Mei-Hsuan Tseng
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital
Hwei-Fang Tien
Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital
Ruey-Hwa Chen
Doctoral Degree Program in Translational Medicine, National Taiwan University and Academia Sinica
Abstract Background Long non-coding RNAs (lncRNAs) represent the majority of cellular transcripts and play pivotal roles in hematopoiesis. However, their clinical relevance in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remains largely unknown. Here, we investigated the functions of HOXB-AS3, a lncRNA located at human HOXB cluster, in the myeloid cells, and analyzed the prognostic significances in patients with AML and MDS. Methods shRNAs were used to downregulate HOXB-AS3 in the cell lines and the effect was evaluated by quantitative polymerase chain reaction. The proliferation of the cell lines was illustrated by proliferation and BrdU flow assays. Further, we retrospectively analyzed the HOXB-AS3 expression in 193 patients with AML and 157 with MDS by microarray analysis, and evaluated its clinical importance. Results Downregulation of HOXB-AS3 suppressed cell proliferation. Mechanistically, HOXB-AS3 potentiated the expressions of several key factors in cell cycle progression and DNA replication without affecting the expressions of HOX genes. In AML, patients with higher HOXB-AS3 expression had shorter survival than those with lower HOXB-AS3 expression (median overall survival (OS), 17.7 months versus not reached, P < 0.0001; median relapse-free survival, 12.9 months versus not reached, P = 0.0070). In MDS, patients with higher HOXB-AS3 expression also had adverse prognosis compared with those with lower HOXB-AS3 expression (median OS, 14.6 months versus 42.4 months, P = 0.0018). The prognostic significance of HOXB-AS3 expression was validated in the TCGA AML cohort and another MDS cohort from our institute. The subgroup analyses in MDS patients showed that higher HOXB-AS3 expressions could predict poor prognosis only in lower-risk (median OS, 29.2 months versus 77.3 months, P = 0.0194), but not higher-risk group. Conclusions This study uncovers a promoting role of HOXB-AS3 in myeloid malignancies and identifies the prognostic value of HOXB-AS3 expression in AML and MDS patients, particularly in the lower-risk group.
