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.

PML /RARα融合蛋白在急性早幼粒细胞白血病（APL）的发生过程中与协同遗传事件协同作用。但是，与PML /RARα协同作用的致癌长非编码RNA（lncRNA）仍未得到充分研究。在这里，我们首先鉴定了一组与病程相关的lncRNA，它们使用来自大量急性髓细胞白血病（AML）患者和正常人群的RNA-seq数据在APL中异常表达。在与发病相关的lncRNA中，一种进化上保守的lncRNA CRNDE（结肠直肠肿瘤的差异表达）引起了我们的注意。我们发现CRNDE在APL的疾病状态中高表达，而在APL的白血病前期则不高，这表明CRNDE可能是与PML /RARα协同促进APL发育的继发事件。功能分析表明，CRNDE抑制可诱导APL细胞分化并抑制其增殖，并延长APL小鼠的生存期。进一步的机理研究表明，CRNDE通过与miR-181家族结合并从而调节其致癌作用NOTCH2。最后，我们发现，高CRNDE表达也显著与相关NPM1突变和促成了分化块NPM1 -mutant AML。总的来说，我们的发现揭示了致癌lncRNA在AML发展中的重要性，并为AML治疗提供了有希望的目标。