Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
EMBO J. 2023 Dec 11;42(24):e112348. doi: 10.15252/embj.2022112348. Epub 2023 Nov 27.
During the last decades, remarkable progress has been made in further understanding the complex molecular regulatory networks that maintain hematopoietic stem cell (HSC) function. Cellular and organismal metabolisms have been shown to directly instruct epigenetic alterations, and thereby dictate stem cell fate, in the bone marrow. Epigenetic regulatory enzymes are dependent on the availability of metabolites to facilitate DNA- and histone-modifying reactions. The metabolic and epigenetic features of HSCs and their downstream progenitors can be significantly altered by environmental perturbations, dietary habits, and hematological diseases. Therefore, understanding metabolic and epigenetic mechanisms that regulate healthy HSCs can contribute to the discovery of novel metabolic therapeutic targets that specifically eliminate leukemia stem cells while sparing healthy HSCs. Here, we provide an in-depth review of the metabolic and epigenetic interplay regulating hematopoietic stem cell fate. We discuss the influence of metabolic stress stimuli, as well as alterations occurring during leukemic development. Additionally, we highlight recent therapeutic advancements toward eradicating acute myeloid leukemia cells by intervening in metabolic and epigenetic pathways.
在过去的几十年中，人们在进一步理解维持造血干细胞（HSC）功能的复杂分子调控网络方面取得了显著进展。细胞和机体代谢已被证明可直接指导骨髓中的表观遗传改变，从而决定干细胞命运。表观遗传调控酶依赖于代谢物的可用性，以促进 DNA 和组蛋白修饰反应。HSC 及其下游祖细胞的代谢和表观遗传特征可因环境干扰、饮食习惯和血液疾病而显著改变。因此，了解调节健康 HSC 的代谢和表观遗传机制有助于发现新的代谢治疗靶点，这些靶点特异性地消除白血病干细胞，同时保留健康的 HSC。在这里，我们深入探讨了调节造血干细胞命运的代谢和表观遗传相互作用。我们讨论了代谢应激刺激的影响，以及在白血病发生过程中发生的变化。此外，我们强调了最近通过干预代谢和表观遗传途径来消除急性髓系白血病细胞的治疗进展。
