近日，英国牛津大学Claus Nerlov研究组发现，C/EBPα和GATA-2突变导致双谱系急性红系白血病的分子机制。相关论文于2020年4月23日在线发表在《癌细胞》杂志上。

研究人员发现，双等位基因Cebpa和Gata2锌指1（ZnF1）的同时突变协同诱导双系急性红系白血病（AEL），并且主要的白血病起始细胞（LIC）群体具有中性粒细胞单核祖细胞（NMP）表型。

在前白血病NMP中，Cebpa和Gata2突变分别通过增加红系转录因子（TF）的表达和红系TF染色质的可及性而协同作用，从而产生了异位的红系潜能。这种红系染色质构象保留在双谱系LIC中。

这些结果表明，由白血病引发的突变所产生的协同转录和表观遗传重编程可以产生新的白血病前体祖细胞，从而确定了所产生白血病的谱系身份。

据了解，急性红系白血病（AEL）通常涉及髓系和红系谱系转化。然而，引起AEL的突变和维持双系白血病表型的细胞仍然未知。

附：英文原文

Author: Cristina Di Genua, Simona Valletta, Mario Buono, Bilyana Stoilova, Connor Sweeney, Alba Rodriguez-Meira, Amit Grover, Roy Drissen, Yiran Meng, Ryan Beveridge, Zahra Aboukhalil, Dimitris Karamitros, Mirjam E. Belderbos, Leonid Bystrykh, Supat Thongjuea, Paresh Vyas, Claus Nerlov

Issue&Volume: 2020-04-23

Abstract: Acute erythroid leukemia (AEL) commonly involves both myeloid and erythroid lineage transformation. However, the mutations that cause AEL and the cell(s) that sustain the bilineage leukemia phenotype remain unknown. We here show that combined biallelic Cebpa and Gata2 zinc finger-1 (ZnF1) mutations cooperatively induce bilineage AEL, and that the major leukemia-initiating cell (LIC) population has a neutrophil-monocyte progenitor (NMP) phenotype. In pre-leukemic NMPs Cebpa and Gata2 mutations synergize by increasing erythroid transcription factor (TF) expression and erythroid TF chromatin access, respectively, thereby installing ectopic erythroid potential. This erythroid-permissive chromatin conformation is retained in bilineage LICs. These results demonstrate that synergistic transcriptional and epigenetic reprogramming by leukemia-initiating mutations can generate neomorphic pre-leukemic progenitors, defining the lineage identity of the resulting leukemia.

DOI: 10.1016/j.ccell.2020.03.022

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30162-8