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.

细胞分化的阻断代表了急性髓性白血病 (AML) 的一个标志，这在很大程度上归因于控制细胞分化的谱系特异性转录因子的功能障碍。然而，AML 中细胞分化程序的替代机制在很大程度上仍未探索。在这里，我们报告混合谱系激酶结构域样蛋白 (MLK​​L) 有助于 AML 中转化的造血祖细胞的细胞分化。使用基因靶向小鼠，我们表明 MLKL 通过控制白血病细胞中的膜通透性来促进粒细胞集落刺激因子 (G-CSF) 的释放。Mlk1 ^-/-造血干细胞和祖细胞释放的 G-CSF 量减少，同时保留了CSF3的能力(G-CSF) mRNA 表达、G-CSF 蛋白翻译和 G-CSF 受体信号传导。MLKL 与早期内体相关，并通过质膜孔的形成控制 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 患者中的MLKL表达显着降低，特别是在那些具有低风险 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释放 G-CSF 来控制 AML 中的骨髓分化。