PI3-kinase deletion promotes myelodysplasia by dysregulating autophagy in hematopoietic stem cells.
PI3-kinase deletion promotes myelodysplasia by dysregulating autophagy in hematopoietic stem cells.
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DOI：
10.1126/sciadv.ade8222
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发表时间：
2023-02-22
期刊：
影响因子：
13.6
通讯作者：
Gritsman, Kira
中科院分区：
文献类型：
--
作者：
Ames, Kristina;Kaur, Imit;Shi, Yang;Tong, Meng M.;Sinclair, Taneisha;Hemmati, Shayda;Glushakow-Smith, Shira G.;Tein, Ellen;Gurska, Lindsay;Steidl, Ulrich;Dubin, Robert;Shan, Jidong;Montagna, Cristina;Pradhan, Kith;Verma, Amit;Gritsman, Kira
骨髓增生异常综合征（MDS）是一种起源于造血干细胞（HSC）的克隆性恶性肿瘤。造血干细胞中MDS发生的机制仍知之甚少。磷脂酰肌醇3-激酶（PI 3 K）/AKT通路在急性髓性白血病中频繁激活，但在MDS中，PI 3 K/AKT常常下调。为了确定PI 3 K下调是否可以扰乱HSC功能，我们在造血细胞中产生了具有Pik 3ca、Pik 3cb和Pik 3cd缺失的三重敲除（TKO）小鼠模型。出乎意料的是，PI 3 K缺乏导致血细胞减少、存活率降低和伴有染色体异常的多谱系发育异常，与MDS的发生一致。TKO HSC表现出受损的自噬，并且药理学自噬诱导改善HSC分化。使用细胞内LC 3和P62流式细胞术和透射电子显微镜，我们还观察到异常的自噬降解患者MDS HSC。因此，我们发现PI 3 K在维持HSC中的自噬通量以保持自我更新和分化之间的平衡并防止MDS起始中具有重要的保护作用。PI 3激酶维持细胞组分的再循环以保护骨髓干细胞功能并防止MDS起始。
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 Pik3ca, Pik3cb, and Pik3cd 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. PI3 kinase maintains recycling of cellular components to preserve bone marrow stem cell function and prevent MDS initiation.
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影响因子：
82.9
作者：
Chen, Jiahao;Kao, Yun-Ruei;Steidl, Ulrich
通讯作者：
Steidl, Ulrich
影响因子：
82.9
作者：
Eppert, Kolja;Takenaka, Katsuto;Dick, John E.
通讯作者：
Dick, John E.
影响因子：
8
作者：
Hemmati, Shayda;Sinclair, Taneisha;Gritsman, Kira
通讯作者：
Gritsman, Kira
影响因子：
64.5
作者：
Adolfsson, J;Månsson, R;Jacobsen, SEW
通讯作者：
Jacobsen, SEW
影响因子：
50.3
作者：
Gewinner C;Wang ZC;Richardson A;Teruya-Feldstein J;Etemadmoghadam D;Bowtell D;Barretina J;Lin WM;Rameh L;Salmena L;Pandolfi PP;Cantley LC
通讯作者：
Cantley LC