Ng Michelle, Verboon Lonneke, Issa Hasan, Bhayadia Raj, Vermunt Marit Willemijn, Winkler Robert, Schüler Leah, Alejo Oriol, Schuschel Konstantin, Regenyi Eniko, Borchert Dorit, Heuser Michael, Reinhardt Dirk, Yaspo Marie-Laure, Heckl Dirk, Klusmann Jan-Henning
Department of Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany.
Department of Pediatrics, Goethe University Frankfurt, 60323 Frankfurt (Main), Germany.
iScience. 2023 Sep 7;26(10):107844. doi: 10.1016/j.isci.2023.107844. eCollection 2023 Oct 20.
The noncoding genome presents a largely untapped source of new biological insights, including thousands of long noncoding RNA (lncRNA) loci. While lncRNA dysregulation has been reported in myeloid malignancies, their functional relevance remains to be systematically interrogated. We performed CRISPRi screens of lncRNA signatures from normal and malignant hematopoietic cells and identified as a myeloid leukemia dependency. Functional dissection suggests an RNA-independent mechanism mediated by two regulatory elements embedded in the locus. Genetic perturbation of these elements triggered a long-range chromatin interaction and downregulation of leukemia dependency genes near the gained interaction sites, as well as overall suppression of cancer dependency pathways. Thus, this study describes a new noncoding myeloid leukemia vulnerability and mechanistic concept for myeloid leukemia. Importantly, perturbation caused strong and selective impairment of leukemia cells of various genetic backgrounds over normal hematopoietic stem and progenitor cells , and depletion of patient-derived xenografts .
非编码基因组是一个尚未被充分挖掘的新生物学见解来源，其中包括数千个长链非编码RNA（lncRNA）基因座。虽然lncRNA失调在髓系恶性肿瘤中已有报道，但其功能相关性仍有待系统研究。我们对正常和恶性造血细胞的lncRNA特征进行了CRISPRi筛选，并确定了一个髓系白血病依赖因素。功能剖析表明，该机制由基因座中嵌入的两个调控元件介导，不依赖RNA。对这些元件的基因干扰引发了长程染色质相互作用，并下调了获得的相互作用位点附近的白血病依赖基因，以及对癌症依赖途径的整体抑制。因此，本研究描述了一种新的非编码髓系白血病易感性和髓系白血病的机制概念。重要的是，这种干扰对各种遗传背景的白血病细胞造成了强烈且选择性的损伤，超过了正常造血干细胞和祖细胞，并且使患者来源的异种移植瘤减少。
