Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
Sci Adv. 2023 Feb 22;9(8):eade8222. doi: 10.1126/sciadv.ade8222.
Myelodysplastic syndrome (MDS) is a clonal malignancy arising in hematopoietic stem cells (HSCs). The mechanisms of MDS initiation in HSCs are still poorly understood. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is frequently activated in acute myeloid leukemia, but in MDS, PI3K/AKT is often down-regulated. To determine whether PI3K down-regulation can perturb HSC function, we generated a triple knockout (TKO) mouse model with , , and deletion in hematopoietic cells. Unexpectedly, PI3K deficiency caused cytopenias, decreased survival, and multilineage dysplasia with chromosomal abnormalities, consistent with MDS initiation. TKO HSCs exhibit impaired autophagy, and pharmacologic autophagy induction improved HSC differentiation. Using intracellular LC3 and P62 flow cytometry and transmission electron microscopy, we also observed abnormal autophagic degradation in patient MDS HSCs. Therefore, we have uncovered an important protective role for PI3K in maintaining autophagic flux in HSCs to preserve the balance between self-renewal and differentiation and to prevent MDS initiation.
骨髓增生异常综合征（MDS）是一种发生在造血干细胞（HSCs）中的克隆性恶性肿瘤。HSCs 中 MDS 起始的机制仍知之甚少。磷酸肌醇 3-激酶（PI3K）/AKT 途径在急性髓性白血病中经常被激活，但在 MDS 中，PI3K/AKT 通常被下调。为了确定 PI3K 下调是否会干扰 HSC 功能，我们在造血细胞中生成了一个三重敲除（TKO）小鼠模型，缺失 、 、 。出乎意料的是，PI3K 缺乏导致血细胞减少、生存能力下降和伴有染色体异常的多谱系发育不良，与 MDS 起始一致。TKO HSCs 表现出自噬受损，而药物诱导的自噬可改善 HSC 分化。通过细胞内 LC3 和 P62 流式细胞术和透射电子显微镜，我们还观察到患者 MDS HSCs 中异常的自噬降解。因此，我们发现 PI3K 在维持 HSCs 中自噬流中具有重要的保护作用，以维持自我更新和分化之间的平衡，防止 MDS 起始。
