Runx1 Loss Minimally Impacts Long-Term Hematopoietic Stem Cells

RUNX1 encodes a DNA binding subunit of the core-binding transcription factors and is frequently mutated in acute leukemia, therapy-related leukemia, myelodysplastic syndrome, and chronic myelomonocytic leukemia. Mutations in RUNX1 are thought to confer upon hematopoietic stem cells (HSCs) a pre-leukemic state, but the fundamental properties of Runx1 deficient pre-leukemic HSCs are not well defined. Here we show that Runx1 deficiency decreases both apoptosis and proliferation, but only minimally impacts the frequency of long term repopulating HSCs (LT-HSCs). It has been variously reported that Runx1 loss increases LT-HSC numbers, decreases LT-HSC numbers, or causes age-related HSC exhaustion. We attempt to resolve these discrepancies by showing that Runx1 deficiency alters the expression of several key HSC markers, and that the number of functional LT-HSCs varies depending on the criteria used to score them. Finally, we identify genes and pathways, including the cell cycle and p53 pathways that are dysregulated in Runx1 deficient HSCs.RUNX1 编码核心结合转录因子的 DNA 结合亚基，且在急性白血病、治疗相关性白血病、骨髓增生异常综合征以及慢性粒单核细胞白血病中频发突变。现有研究认为，RUNX1 突变可使造血干细胞（hematopoietic stem cells, HSCs）获得前白血病状态，但 RUNX1 缺陷型前白血病造血干细胞的基本特性尚未明确。本研究发现，RUNX1 缺陷可同时降低细胞凋亡与增殖水平，但仅对长期重建造血潜能的造血干细胞（long term repopulating HSCs, LT-HSCs）的频率产生微弱影响。既往研究对 RUNX1 缺失的影响存在诸多分歧：有报道称其可增加 LT-HSC 数量，亦有报道称其会减少 LT-HSC 数量，还有研究指出其可导致年龄相关性造血干细胞耗竭。本研究通过证实 RUNX1 缺陷可改变多种关键造血干细胞标志物的表达，且功能性 LT-HSC 的数量会随评分标准的不同而发生变化，试图解决上述研究分歧。最后，本研究还鉴定出 RUNX1 缺陷造血干细胞中存在表达失调的基因与通路，包括细胞周期通路与 p53 通路。