Runx1 deficiency decreases ribosome biogenesis and confers stress resistance to hematopoietic stem and progenitor cells. Mus musculus

The transcription factor RUNX1 is frequently mutated in myelodysplastic syndrome and leukemia. RUNX1 mutations can be early events, creating pre-leukemic stem cells that expand in the bone marrow. Here we show that, counter-intuitively, Runx1 deficient hematopoietic stem and progenitor cells (HSPCs) have a slow growth, low biosynthetic, small cell phenotype and markedly reduced ribosome biogenesis (Ribi). The reduced Ribi involves decreased levels of rRNA and many mRNAs encoding ribosome proteins. Runx1 appears to directly regulate Ribi; Runx1 is enriched on the promoters of genes encoding ribosome proteins, and binds the ribosomal DNA repeats. Runx1 deficient HSPCs have lower p53 levels, reduced apoptosis, an attenuated unfolded protein response, and accordingly are resistant to genotoxic and endoplasmic reticulum stress. The low biosynthetic activity and corresponding stress resistance provides a selective advantage to Runx1 deficient HSPCs, allowing them to expand in the bone marrow and outcompete normal HSPCs. Overall design: Comparison of the phenotypic and molecular properties of normal (Runx1f/f, or WT) versus Runx1 deficient (Mut) hematopoietic stem cells.

转录因子RUNX1（transcription factor RUNX1）在骨髓增生异常综合征（myelodysplastic syndrome）与白血病（leukemia）中频发突变。RUNX1突变可作为疾病早期事件，催生可在骨髓中扩增的白血病前干细胞。本研究揭示与直觉相悖的现象：RUNX1缺陷型造血干祖细胞（hematopoietic stem and progenitor cells，HSPCs）呈现生长缓慢、生物合成活性低下、细胞体积偏小的表型，且核糖体生物发生（ribosome biogenesis，Ribi）显著受抑。此类核糖体生物发生受损表现为核糖体RNA（rRNA）水平降低，以及大量编码核糖体蛋白的信使RNA（mRNA）表达水平下调。RUNX1似乎可直接调控核糖体生物发生过程：其在核糖体蛋白编码基因的启动子区域存在富集，并可结合核糖体DNA重复序列。RUNX1缺陷型HSPCs的p53蛋白（p53）水平更低，细胞凋亡（apoptosis）减少，未折叠蛋白反应（unfolded protein response）减弱，因此对遗传毒性应激（genotoxic stress）与内质网应激（endoplasmic reticulum stress）产生抗性。这种低生物合成活性与对应的应激抗性为RUNX1缺陷型HSPCs提供了选择优势，使其可在骨髓中扩增并排挤正常HSPCs。总体实验设计：对比正常（Runx1f/f或野生型（wild type，WT））与RUNX1缺陷型（Mut）造血干细胞的表型与分子特性。