Medical Department III for Hematology and Oncology, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Department of Internal Oncology, Jiangsu Cancer Hospital (Nanjing Medical University Affiliated Cancer Hospital) and Jiangsu Institute of Cancer Research, Nanjing, China.
Cell Death Differ. 2021 Dec;28(12):3235-3250. doi: 10.1038/s41418-021-00811-1. Epub 2021 Jun 2.
The blockade of cellular differentiation represents a hallmark of acute myeloid leukemia (AML), which is largely attributed to the dysfunction of lineage-specific transcription factors controlling cellular differentiation. However, alternative mechanisms of cellular differentiation programs in AML remain largely unexplored. Here we report that mixed lineage kinase domain-like protein (MLKL) contributes to the cellular differentiation of transformed hematopoietic progenitor cells in AML. Using gene-targeted mice, we show that MLKL facilitates the release of granulocyte colony-stimulating factor (G-CSF) by controlling membrane permeabilization in leukemic cells. Mlkl hematopoietic stem and progenitor cells released reduced amounts of G-CSF while retaining their capacity for CSF3 (G-CSF) mRNA expression, G-CSF protein translation, and G-CSF receptor signaling. MLKL associates with early endosomes and controls G-CSF release from intracellular storage by plasma membrane pore formation, whereas cell death remained unaffected by loss of MLKL. Of note, MLKL expression was significantly reduced in AML patients, specifically in those with a poor-risk AML subtype. Our data provide evidence that MLKL controls myeloid differentiation in AML by controlling the release of G-CSF from leukemic progenitor cells.
细胞分化受阻是急性髓细胞白血病（AML）的一个显著特征，其主要归因于控制细胞分化的谱系特异性转录因子功能障碍。然而，AML 中细胞分化程序的其他机制在很大程度上仍未被探索。在这里，我们报告混合谱系激酶结构域样蛋白（MLKL）有助于 AML 中转化造血祖细胞的细胞分化。通过使用基因靶向小鼠，我们发现 MLKL 通过控制白血病细胞的膜通透性来促进粒细胞集落刺激因子（G-CSF）的释放。Mlkl 造血干细胞和祖细胞释放的 G-CSF 减少，但仍保留其 CSF3（G-CSF）mRNA 表达、G-CSF 蛋白翻译和 G-CSF 受体信号的能力。MLKL 与早期内体相关联，并通过形成质膜孔控制 G-CSF 从细胞内储存中的释放，而细胞死亡不受 MLKL 缺失的影响。值得注意的是，AML 患者的 MLKL 表达明显降低，特别是在具有不良风险 AML 亚型的患者中。我们的数据提供了证据，表明 MLKL 通过控制白血病祖细胞中 G-CSF 的释放来控制 AML 中的髓样分化。
