Autophagy limits proliferation and glycolytic metabolism in acute myeloid leukemia.
Autophagy limits proliferation and glycolytic metabolism in acute myeloid leukemia.
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DOI：
10.1038/cddiscovery.2015.8
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发表时间：
2015-08-17
影响因子：
7
通讯作者：
Simon AK
中科院分区：
文献类型：
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作者：
Watson AS;Riffelmacher T;Stranks A;Williams O;De Boer J;Cain K;MacFarlane M;McGouran J;Kessler B;Khandwala S;Chowdhury O;Puleston D;Phadwal K;Mortensen M;Ferguson D;Soilleux E;Woll P;Jacobsen SE;Simon AK
自噬减少会导致恶性肿瘤；然而，目前尚不清楚自噬如何影响肿瘤生长。急性髓系白血病 (AML) 是解决这一问题的理想模型，因为 (i) 患者样本易于获取，(ii) 发生转化的造血干细胞和祖细胞 (HSPC) 已得到充分表征，(iii) HSPC 中关键自噬基因 Atg7 的丢失会导致小鼠出现致命的白血病前表型。在这里，我们证明 Atg5 的缺失会导致与 Atg7 的缺失相同的 HSPC 表型，证实了自噬在 HSPC 调节中的一般作用。与更定型/成熟的造血细胞相比，健康的人类和小鼠 HSPC 显示出增强的基础自噬通量，限制了这一长寿群体中的线粒体损伤和活性氧。综上所述，与我们之前的发现相比，这些数据与自噬限制性白血病转化相一致。与此相一致的是，在人类 AML 中通常被删除的染色体区域内发现了自噬基因丢失。此外，人类 AML 原始细胞显示自噬基因表达减少，并且随着不健康线粒体的积累，自噬通量减少，表明自噬缺陷可能对人类 AML 有益。至关重要的是，在 AML 的 MLL-ENL 模型中，自噬的杂合性丧失导致体外增殖增加、体内糖酵解转变和更具侵袭性的白血病。由于在多种其他恶性肿瘤中也发现了自噬基因丢失，这些发现表明自噬水平较低，为肿瘤生长提供了总体优势。
Decreased autophagy contributes to malignancies; however, it is unclear how autophagy has an impact on tumor growth. Acute myeloid leukemia (AML) is an ideal model to address this as (i) patient samples are easily accessible, (ii) the hematopoietic stem and progenitor cells (HSPC) where transformation occurs is well characterized and (iii) loss of the key autophagy gene Atg7 in HSPCs leads to a lethal pre-leukemic phenotype in mice. Here we demonstrate that loss of Atg5 results in an identical HSPC phenotype as loss of Atg7, confirming a general role for autophagy in HSPC regulation. Compared with more committed/mature hematopoietic cells, healthy human and mouse HSPCs displayed enhanced basal autophagic flux, limiting mitochondrial damage and reactive oxygen species in this long-lived population. Taken together, with our previous findings these data are compatible with autophagy-limiting leukemic transformation. In line with this, autophagy gene losses are found within chromosomal regions that are commonly deleted in human AML. Moreover, human AML blasts showed reduced expression of autophagy genes and displayed decreased autophagic flux with accumulation of unhealthy mitochondria, indicating that deficient autophagy may be beneficial to human AML. Crucially, heterozygous loss of autophagy in an MLL–ENL model of AML led to increased proliferation in vitro, a glycolytic shift and more aggressive leukemias in vivo. With autophagy gene losses also identified in multiple other malignancies, these findings point to low autophagy, providing a general advantage for tumor growth.