美国纽约大学PerlmuttIannis Aifantis、Eric Wang等研究人员合作通过表面抗原引导的CRISPR筛选鉴定出髓样白血病分化的调控因子。2021年1月14日，《细胞—干细胞》杂志在线发表了这项成果。

为了确定分化疗法的靶标，研究人员应用了基于细胞表面的整合CRISPR平台来评估与维持白血病细胞未分化状态有关的基因。研究人员确定RNA结合蛋白ZFP36L2是急性髓细胞性白血病（AML）维持和分化的关键调节因子。

从机制上讲，ZFP36L2与关键髓样成熟基因的3'非翻译区（包括ZFP36旁系同源物）相互作用，从而促进其mRNA降解并抑制终末髓细胞分化。ZFP36L2的遗传抑制可恢复这些靶向转录物的mRNA稳定性，并最终触发白血病细胞中的髓样分化。

几名原发性AML患者的表观基因组分析显示，ZFP36L2附近的增强子模块与不同的AML细胞状态相关，这建立了相应的表观遗传和转录后机制，进而影响了白血病的分化。

据悉，缺乏细胞分化是许多人类癌症的标志，包括AML。克服这种分化障碍的策略是一种治疗AML的方法。

附：英文原文

Title: Surface antigen-guided CRISPR screens identify regulators of myeloid leukemia differentiation

Author: Eric Wang, Hua Zhou, Bettina Nadorp, Geraldine Cayanan, Xufeng Chen, Anna H. Yeaton, Sofia Nomikou, Matthew T. Witkowski, Sonali Narang, Andreas Kloetgen, Palaniraja Thandapani, Niklas Ravn-Boess, Aristotelis Tsirigos, Iannis Aifantis

Issue&Volume: 2021-01-14

Abstract: Lack of cellular differentiation is a hallmark of many human cancers, including acutemyeloid leukemia (AML). Strategies to overcome such a differentiation blockade arean approach for treating AML. To identify targets for differentiation-based therapies,we applied an integrated cell surface-based CRISPR platform to assess genes involvedin maintaining the undifferentiated state of leukemia cells. Here we identify theRNA-binding protein ZFP36L2 as a critical regulator of AML maintenance and differentiation.Mechanistically, ZFP36L2 interacts with the 3′ untranslated region of key myeloidmaturation genes, including the ZFP36 paralogs, to promote their mRNA degradationand suppress terminal myeloid cell differentiation. Genetic inhibition of ZFP36L2restores the mRNA stability of these targeted transcripts and ultimately triggersmyeloid differentiation in leukemia cells. Epigenome profiling of several individualswith primary AML revealed enhancer modules near ZFP36L2 that associated with distinctAML cell states, establishing a coordinated epigenetic and post-transcriptional mechanismthat shapes leukemic differentiation.

DOI: 10.1016/j.stem.2020.12.005

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30589-0