Cell · 2025
Inhibition of heme biosynthesis triggers cuproptosis in acute myeloid leukemia.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Lewis Alexander C, Gruber Emily, Franich Rheana, Armstrong Jessica, Kelly Madison J, Opazo Carlos M, Low Yau C, Flippe Léa, Wijanarko Kevin, Rowe Caitlin L, Mawal Celeste H, Birrell Alexandra, So Joan, Vaidyanathan Srimayee, Ting Keziah, Semcesen Liana N, Last Karena, Ang Ching-Seng, Pomilio Giovanna, Brown Fiona C, Wei Andrew H, Powell Jason A, Ng Elizabeth S, Frazier Ann E, McArthur Kate, Lalaoui Najoua, Stroud David A, Brown Kristin K, Johnstone Ricky W, Kats Lev M
Аннотация
The ubiquitous metabolite heme has diverse enzymatic and signaling functions in most mammalian cells. Through integrated analyses of mouse models, human cell lines, and primary patient samples, we identify de novo heme biosynthesis as a selective dependency in acute myeloid leukemia (AML). The dependency is underpinned by a propensity of AML cells, and especially leukemic stem cells (LSCs), to downregulate heme biosynthesis enzymes (HBEs), which promotes their self-renewal. Inhibition of HBEs causes the collapse of mitochondrial Complex IV and dysregulates the copper-chaperone system, inducing cuproptosis, a form of programmed cell death brought about by the oligomerization of lipoylated proteins by copper. Moreover, we identify pathways that are synthetic lethal with heme biosynthesis, including glycolysis, which can be leveraged for combination strategies. Altogether, our work uncovers a heme rheostat that is connected to gene expression and drug sensitivity in AML and implicates HBE inhibition as a trigger of cuproptosis.