LncRNA BC200/miR-150-5p/MYB positive feedback loop promotes the malignant proliferation of myelodysplastic syndrome

Zhaoping Liu,Jing Liu,Fuxiang Zheng,Bin Hu,Shunling Yuan,Pengfei Cao,Zi Wang,Long Liang,Hui Li,Xiaojuan Xiao,Ji Zhang,Feng Wen,Pan Wang,Yanyan Wang,Lin Zhu

doi:10.1038/s41419-022-04578-2

Abstract

Myelodysplastic syndrome (MDS) is a group of heterogeneous hematologic malignancies with a risk of transformation to acute myeloid leukemia. Understanding the molecular mechanisms of the specific roles of long noncoding RNAs (lncRNAs) in MDS would create novel ways to identify diagnostic and therapeutic targets. The lncRNA BC200 is upregulated and acts as an oncogene in various cancers; however, its expression, clinical significance, and roles in MDS remain unclear. Here, we found that BC200 was highly expressed in MDS patients compared with normal individuals. Knockdown of BC200 inhibited MDS cell proliferation, colony formation, and cell cycle progression in vitro and suppressed the growth and invasiveness of MDS cells in vivo. Mechanistic investigations revealed that BC200 functioned as a miRNA sponge to positively regulate the expression of MYB through sponging miR-150-5p and subsequently promoted malignant proliferation of MDS cells. Conversely, we found that BC200 was a direct transcriptional target of MYB, and knockdown of MYB abolished the oncogenic effect of BC200/miR-150-5p. Taken together, our results revealed that the BC200/miR-150-5p/MYB positive feedback loop promoted the proliferation of MDS cells and is expected to be a potential biomarker and therapeutic target in MDS.

Highlights

Myelodysplastic syndrome (MDS) is a clonal hematological malignancy characterized by ineffective hematopoiesis, progressive cytopenia and clonal evolution to acute myeloid leukemia [1, 2]
Cell proliferation was analyzed by Cell Counting Kit-8 (CCK-8), Ethynyl deoxyuridine (Edu) incorporation, colony formation assays, and Fluorescence-activated cell sorting (FACS) analysis
Edu incorporation and colony formation assays indicated that knockdown of BC200 inhibited the malignant proliferation ability of SKM-1 and MDS-L cells compared to the paired negative were blinded to the randomization

Summary

Introduction

Myelodysplastic syndrome (MDS) is a clonal hematological malignancy characterized by ineffective hematopoiesis, progressive cytopenia and clonal evolution to acute myeloid leukemia [1, 2]. The pathophysiology of MDS is a multistep process involving cytogenetic changes, gene mutations, or both. Malignant clonal hematopoietic cells often coexist and compete with normal hematopoietic cells for a considerable period of time in the bone marrow (BM) of MDS patients. When malignant clonal cells become dominant in BM, the disease progresses to AML [4]. Patients with MDS are usually at an advanced age and may have comorbidities that make them ineligible for these treatment options due to excessive toxicity [5]. Better understanding of the pathogenesis of MDS is crucial for developing novel and effective treatment strategies against this fatal disease

Methods

Results

Conclusion