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.

IL6 pretreatment promotes chemosensitivity by eliminating quiescent cancer (stem) cells in lung adenocarcinoma Dear Editor, Lung cancer is one of the most devastating malignancy globally. Despite great development of target and immunotherapies, cytotoxic chemotherapy is still regarded as the backbone for lung cancer treatment. Clonal heterogeneity and selection pressure from chemotherapy together contribute to chemoresistance. 1 Cancer stem cells (CSCs) are a subpopulation of cancer cells that have the capabilities of self-renewability, tumor initiation, and therapeutic resistance. Cell quiescence is defined as one of the hallmarks of CSCs 2 ; thus, elimination of quiescent tumor cells provides a practical approach for cancer treatment, aiming to lower the chances of recurrence (or at least extends the remission time). 3 IL6 pretreatment promotes entry into cell cycle, which significantly reverses the chemo-resistant by reducing quiescent cancer (stem) cells in Cisplatin (cDDP) chemotherapy. The effect of IL6 pretreatment depends on the existence of TFAP2A. Lung adenocarcinoma tissues were collected from surgical resections for primary lung cancer cell (PLCC) preparation. The PPLCs were stained with CSC surface markers and sorted to CSCs (CD133 + /CD44 + /CD24 −), non-CSCs (CD133 − /CD44 − /CD24 +), and control (full populations, sorted without selection) subpopulations 4-8 (Figure 1A). The CSC subgroup showed accumulation of oligopotential cell population as measured by an increase in the number of colony formation units, (Figure 1B, Figure S1). Also, CSCs have the advantage of forming bigger dense colonies (Figure 1C). In Figures S2-S5, the percentage of CSCs, cell cycle distribution, and cell death were measured, and we found that the IL6 pretreatment contributed to the expansion of CSCs and also increased the chemosensitivity by eliminating G0 cells. Thus, the biological differences between continuously fed IL6 and IL6 pretreatment for chemotherapy were further explored. PLCCs were collected for measuring the CSC percentage. Cell cycle distribution staining at different time points after 48 hours of IL6 treatment showed This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.