Oncogenic role of lncRNA CRNDE in acute promyelocytic leukemia and NPM1-mutant acute myeloid leukemia

Xuefei Ma,Kankan Wang,Wei Zhang,Wen Jin,Ming Zhao,Shufen Li

doi:10.1038/s41420-020-00359-y

Abstract

The PML/RARα fusion protein acts in concert with cooperative genetic events in the development of acute promyelocytic leukemia (APL). However, oncogenic long non-coding RNAs (lncRNAs) cooperating with PML/RARα remain under-explored. Here, we first identified a set of pathogenesis-related lncRNAs, aberrantly expressed in APL using RNA-seq data from a large cohort of acute myeloid leukemia (AML) patients and normal counterparts. Among the pathogenesis-related lncRNAs, one of the evolutionarily conservative lncRNAs CRNDE (Colorectal Neoplasia Differentially Expressed) drew our attention. We found that CRNDE was highly expressed in the disease state but not in the preleukemic stage of APL, suggesting that CRNDE might be a secondary event coordinating with PML/RARα to promote APL development. Functional analysis showed that CRNDE knockdown induced differentiation and inhibited proliferation of APL cells, and prolonged survival of APL mice. Further mechanistic studies showed that CRNDE elicited its oncogenic effects through binding the miR-181 family and thereby regulating NOTCH2. Finally, we found that high CRNDE expression was also significantly correlated with NPM1 mutations and contributed to the differentiation block in NPM1-mutant AML. Collectively, our findings shed light on the importance of oncogenic lncRNAs in the development of AML and provide a promising target for AML therapy.

Highlights

Leukemia development involves a series of complex and multifactorial events that lead to dysregulation of genes involved in differentiation, proliferation, and apoptosis of leukemia cells
We identified a series of pathogenesisrelated long non-coding RNAs (lncRNAs) in acute promyelocytic leukemia (APL) by comparing a large number of RNA-seq data from acute myeloid leukemia (AML) and normal bone marrows
Samples (29 APL and 350 non-APL AML) and 21 normal counterparts from two cohorts of clinical AML patients to explore lncRNAs that may contribute to the pathogenesis of APL

Summary

Introduction

Leukemia development involves a series of complex and multifactorial events that lead to dysregulation of genes involved in differentiation, proliferation, and apoptosis of leukemia cells. Extensive studies have focused on the roles of protein-coding genes, which constitute two percent of the human genome, in the initiation, maintenance, and development of leukemia[1,2]. Intensive studies have been made to elucidate the roles of PML/RARα in malignant transformation and differentiation block at the promyelocytic stage of myelopoiesis[5]. Based on murine APL models, it appears that PML/RARα alone is not sufficient to cause leukemia, and cooperating events are required for the Official journal of the Cell Death Differentiation Association. Most of our knowledge about the cooperating events during APL development has come from the studies conducted on protein-coding genes, and the function of lncRNAs involved in APL leukemogenesis is still largely unknown

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Conclusion