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C/EBPα and GATA-2 Mutations Induce Bilineage Acute Erythroid Leukemia through Transformation of a Neomorphic Neutrophil-Erythroid Progenitor.
Cancer Cell ( IF 48.8 ) Pub Date : 2020-04-23 , DOI: 10.1016/j.ccell.2020.03.022
Cristina Di Genua 1 , Simona Valletta 1 , Mario Buono 1 , Bilyana Stoilova 2 , Connor Sweeney 2 , Alba Rodriguez-Meira 1 , Amit Grover 1 , Roy Drissen 1 , Yiran Meng 1 , Ryan Beveridge 1 , Zahra Aboukhalil 2 , Dimitris Karamitros 2 , Mirjam E Belderbos 3 , Leonid Bystrykh 4 , Supat Thongjuea 5 , Paresh Vyas 2 , Claus Nerlov 1
Affiliation  

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.

中文翻译:

C/EBPα 和 GATA-2 突变通过新生中性粒细胞-红细胞祖细胞的转化诱导双系急性红细胞白血病。

急性红细胞白血病 (AEL) 通常涉及骨髓和红细胞谱系转化。然而,导致 AEL 的突变和维持双系白血病表型的细胞仍然未知。我们在此表明​​,组合的双等位基因 Cebpa 和 Gata2 锌指 1 (ZnF1) 突变协同诱导双系 AEL,并且主要的白血病起始细胞 (LIC) 群体具有中性粒细胞-单核细胞祖细胞 (NMP) 表型。在白血病前期 NMP 中,Cebpa 和 Gata2 突变通过分别增加红细胞转录因子 (TF) 表达和红细胞 TF 染色质通路而协同作用,从而产生异位红细胞潜能。这种红细胞允许的染色质构象保留在双系 LIC 中。
更新日期:2020-04-23
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