Laboratory of Fundamental and Applied Bioenergetics (LBFA), University Grenoble Alpes, INSERM U1055, 38000 Grenoble, France.
Department of Biological Hematology, Institute of Biology and Pathology, Hospital of Grenoble Alpes (CHUGA), CS 20217, 38043 Grenoble, CEDEX a9, France.
Int J Mol Sci. 2023 Sep 19;24(18):14307. doi: 10.3390/ijms241814307.
Acute myeloid leukemia (AML) remains a disease of gloomy prognosis despite intense efforts to understand its molecular foundations and to find efficient treatments. In search of new characteristic features of AML blasts, we first examined experimental conditions supporting the amplification of hematological CD34 progenitors ex vivo. Both AML blasts and healthy progenitors heavily depended on iron availability. However, even if known features, such as easier engagement in the cell cycle and amplification factor by healthy progenitors, were observed, multiplying progenitors in a fully defined medium is not readily obtained without modifying their cellular characteristics. As such, we measured selected molecular data including mRNA, proteins, and activities right after isolation. Leukemic blasts showed clear signs of metabolic and signaling shifts as already known, and we provide unprecedented data emphasizing disturbed cellular iron homeostasis in these blasts. The combined quantitative data relative to the latter pathway allowed us to stratify the studied patients in two sets with different iron status. This categorization is likely to impact the efficiency of several therapeutic strategies targeting cellular iron handling that may be applied to eradicate AML blasts.
尽管人们在深入研究急性髓细胞白血病（AML）的分子基础和寻找有效治疗方法方面做出了巨大努力，但这种疾病的预后仍然不容乐观。为了寻找 AML 原始细胞的新特征，我们首先检查了支持体外扩增血液学 CD34 祖细胞的实验条件。AML 原始细胞和健康祖细胞都严重依赖铁的供应。然而，即使观察到了已知的特征，如健康祖细胞更容易进入细胞周期和扩增因子，在不改变其细胞特征的情况下，在完全定义的培养基中扩增祖细胞也不容易实现。因此，我们在分离后立即测量了包括 mRNA、蛋白质和活性在内的选定分子数据。正如已经知道的那样，白血病原始细胞表现出明显的代谢和信号转导变化的迹象，我们提供了前所未有的数据，强调了这些原始细胞中细胞内铁稳态的紊乱。与后一种途径相关的综合定量数据使我们能够将研究的患者分为两组，具有不同的铁状态。这种分类可能会影响针对细胞铁处理的几种治疗策略的效率，这些策略可能被应用于根除 AML 原始细胞。
