MALNC: A new mutant NPM1/IDH2R140 and PML-RARA-associated lncRNA with impact on AML cell proliferation, maturation and drug response [ChIRP-seq]

As the non-coding genome remains poorly characterized in acute myeloid leukemia (AML), we aimed to identify and functionally characterize novel long non-coding RNAs (lncRNAs) relevant to AML biology and treatment. We first identified lncRNAs overexpressed in AML blasts and discovered a novel lncRNA, which we named myeloid and AML-associated intergenic long non-coding RNA (MALNC). MALNC is overexpressed in AML, particularly in cases with the PML-RARA fusion or IDH2R140/NPM1 co-mutations, and is associated with a distinct gene expression profile. Functional studies showed that MALNC knockout impairs AML cell proliferation and colony formation, enhances ATRA-induced differentiation, and sensitizes cells to arsenic trioxide. Transcriptomic analysis revealed that MALNC loss alters the expression of retinoic acid pathway genes, and chromatin binding studies showed that MALNC binds to genes related to the retinoic acid and Rho GTPase pathways. In conclusion, we have identified MALNC as a novel lncRNA that promotes leukemic cell proliferation, counteracts ATRA-induced differentiation, and modulates drug sensitivity in AML. Overall design: NB4 cells were used to evaluate the DNA-binding sites of the long non-coding RNA MALNC through ChIRP-seq analysis.

鉴于急性髓系白血病（AML）中非编码基因组的研究仍有待深入阐明，本研究旨在筛选并功能鉴定与AML生物学特性及治疗策略相关的新型长链非编码RNA（lncRNAs）。
我们首先在AML母细胞中筛选得到过表达的lncRNAs，并发现了一种新型长链非编码RNA，将其命名为骨髓系与AML相关的基因间区长链非编码RNA（myeloid and AML-associated intergenic long non-coding RNA, MALNC）。
MALNC在AML患者样本中呈过表达状态，尤其在携带PML-RARA融合基因或IDH2R140/NPM1共突变的病例中更为显著，且与独特的基因表达谱密切相关。
功能实验结果显示，敲除MALNC可抑制AML细胞的增殖与集落形成能力，增强全反式维甲酸（ATRA）诱导的细胞分化，并提高细胞对三氧化二砷的药物敏感性。
转录组分析表明，MALNC缺失会改变视黄酸通路相关基因的表达；染色质结合实验则证实，MALNC可结合视黄酸通路与Rho GTP酶通路相关的靶基因。
综上，本研究鉴定出MALNC是一种新型长链非编码RNA，可促进白血病细胞增殖、拮抗ATRA诱导的细胞分化，并调控AML细胞的药物敏感性。
总体实验设计：以NB4细胞为模型，通过ChIRP-seq分析该长链非编码RNA MALNC的DNA结合位点。