爱丁堡大学Kamil R. Kranc课题组宣布他们研究出RNA m⁶A读码器YTHDF2选择性损害急性髓性白血病的肿瘤干细胞。该研究于2019年7月发表于国际一流学术期刊《细胞—干细胞》杂志上。

研究团队发现，mRNA m⁶A读码器 YTHDF2在人类AML的广谱中过度表达，是鼠和人类AML疾病发生和传播所必需的。YTHDF2降低多种包含m⁶A转录本的半衰期，有助于白血病干细胞（LSC）功能的完整性，包括肿瘤坏死因子受体Tnfrsf2，它在YTHDF2缺失的LSCs启动细胞中上调细胞凋亡。YTHDF2对于正常的HSC功能并不是必需的，YTHDF2缺乏实际上增强了HSC活性。因此，研究人员认为YTHDF2是一种独特的治疗靶点，它在促进HSC扩张的同时选择性地抑制LSCs。

据悉，急性髓系白血病(AML)是由造血干细胞(HSCs)和原始祖细胞组成的一种侵袭性克隆性疾病。

附：英文原文

Title: Targeting the RNA m6A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia

Author:Jasmin Paris, Marcos Morgan, Joana Campos, Gary J. Spencer, Alena Shmakova, Ivayla Ivanova, Christopher Mapperley, Hannah Lawson, David A. Wotherspoon, Catarina Sepulveda, Milica Vukovic, Lewis Allen, Annika Sarapuu, Andrea Tavosanis, Amelie V. Guitart, Arnaud Villacreces, Christian Much, Junho Choe, Ali Azar, Louie N. van de Lagemaat, Douglas Vernimmen, Ali Nehme, Frederic Mazurier, Tim C.P. Somervaille, Richard I. Gregory Dónal O’Carroll

Issue&Volume:Volume 25 Issue 1

Abstract: Acute myeloid leukemia (AML) is an aggressive clonal disorder of hematopoietic stem cells (HSCs) and primitive progenitors that blocks their myeloid differentiation, generating self-renewing leukemic stem cells (LSCs). Here, we show that the mRNA m6A reader YTHDF2 is overexpressed in a broad spectrum of human AML and is required for disease initiation as well as propagation in mouse and human AML. YTHDF2 decreases the half-life of diverse m6A transcripts that contribute to the overall integrity of LSC function, including the tumor necrosis factor receptor Tnfrsf2, whose upregulation in Ythdf2-deficient LSCs primes cells for apoptosis. Intriguingly, YTHDF2 is not essential for normal HSC function, with YTHDF2 deficiency actually enhancing HSC activity. Thus, we identify YTHDF2 as a unique therapeutic target whose inhibition selectively targets LSCs while promoting HSC expansion.

DOI: https://doi.org/10.1016/j.stem.2019.03.021

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30120-1