Unraveling the Link between Class 1A PI3-Kinase, Autophagy, and Myelodysplasia.
Unraveling the Link between Class 1A PI3-Kinase, Autophagy, and Myelodysplasia.
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揭示 1A 类 PI3 激酶、自噬和骨髓增生异常之间的联系。
DOI：
10.1080/15548627.2023.2221922
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发表时间：
2023
期刊：
影响因子：
13.3
通讯作者：
Gritsman,Kira
中科院分区：
文献类型：
--
作者：
Ames,Kristina;Gritsman,Kira
骨髓增生异常综合征(MDS)是一种由造血干细胞(HSCs)发展而来的克隆性恶性肿瘤，但MDS的发病机制尚不清楚。在MDS中，磷脂酰肌醇3-激酶/蛋白激酶B(PI3K/AKT)信号转导通路常处于失调状态。为了研究PI3K失活对HSC功能的影响，我们建立了一个小鼠模型，在该模型中，三个IA类PI3K基因在造血细胞中被缺失。令人惊讶的是，PI3K缺乏导致细胞减少，存活率降低，多系发育不良伴染色体异常，这与MDS的启动一致。PI3K缺陷的HSC损害了自噬，自噬诱导试剂的药物治疗促进了HSC的分化。此外，在MDS患者的HSCs中也观察到类似的自噬降解缺陷。因此，我们的研究发现，IA类PI3K在维持HSCs自噬通量以维持自我更新和分化之间的平衡方面具有重要的保护作用。
Myelodysplastic syndrome (MDS) is a clonal malignancy that develops from hematopoietic stem cells (HSCs), but the underlying mechanisms of MDS initiation are not well understood. The phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway is often dysregulated in MDS. To investigate how PI3K inactivation affects HSC function, we generated a mouse model in which three Class IA PI3K genes were deleted in hematopoietic cells. Surprisingly, PI3K deficiency caused cytopenias, reduced survival, and multilineage dysplasia with chromosomal abnormalities, consistent with MDS initiation. PI3K-deficient HSCs had impaired autophagy, and pharmacologic treatment with autophagy-inducing reagents improved HSC differentiation. Furthermore, a similar autophagic degradation defect was observed in MDS patient HSCs. Therefore, our study uncovered a crucial protective role for Class IA PI3K in maintaining autophagic flux in HSCs to preserve the balance between self-renewal and differentiation.