Abstract

Relapse of acute myeloid leukemia (AML) has a very poor prognosis and remains a common cause of treatment failure in patients with this disease. AML relapse is partially driven by the chemoresistant nature of leukemia stem cells (LSCs), which remains poorly understood, and our study aimed at elucidating the underlying mechanism. Accumulating evidences show that long noncoding RNAs (lncRNAs) play a crucial role in AML development. Herein, the lncRNA, LINC00152, was identified to be highly expressed in CD34+ LSCs and found to regulate the self-renewal of LSCs derived from AML patients. Importantly, LINC00152 upregulation was correlated with the expression of 16 genes within a 17-gene LSC biomarker panel, which contributed to the accurate prediction of initial therapy resistance in AML. Knockdown of LINC00152 markedly increased the drug sensitivity of leukemia cells. Furthermore, LINC00152 expression was found to be correlated with poly (ADP-ribose) polymerase 1 (PARP1) expression in AML, whereas LINC00152 knockdown significantly decreased the expression of PARP1. Upregulation of LINC00152 or PARP1 was associated with poor prognosis in AML patients. Collectively, these data highlight the importance and contribution of LINC00152 in the regulation of self-renewal and chemoresistance of LSCs in AML.

Highlights

  • Acute myeloid leukemia (AML) is a heterogeneous and deadly disease characterized by aberrant myeloid lineage cell proliferation and differentiation [1]

  • CD34+CD38− cells possessed a markedly stronger capacity for colony formation than CD34−CD38+ cells derived from paired 15 acute myeloid leukemia (AML) patients (P = 5.4 × 10−13) (Figure 1B). Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) showed that LINC00152 was highly expressed in CD34+CD38− cells compared with CD34−CD38+ subpopulations (P = 0.02) (Figure 1C)

  • High expression of LINC00152 was associated with poor AML patient survival (Figure 1D), suggesting that LINC00152 may be a potential prognostic marker for AML

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Summary

Introduction

Acute myeloid leukemia (AML) is a heterogeneous and deadly disease characterized by aberrant myeloid lineage cell proliferation and differentiation [1]. Most AML patients achieve remission, up to 70% of adults and 30% of pediatric patients do not survive beyond 5 years after the initial clinical response due to relapse [2]. The relapse of AML patients has been attributed to the pre-existence of chemoresistant leukemia stem cells (LSCs) [3, 4]. The mechanisms underlying LSC-mediated leukemia relapse have not been elucidated. Leukemia cells differentiate from LSCs [5], which have the capacity to initiate leukemia in immunocompromised mice. It is warranted to investigate potential factors contributing to the self-renewal and chemoresistant nature of LSCs

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