MLKL promotes cellular differentiation in myeloid leukemia by facilitating the release of G-CSF

Wang, Xin; Ros, Uris; Agrawal, Deepti; Keller, Eva C.; Slotta-Huspenina, Julia; Dill, Veronika; Shen, Bo; Shi, Run; Herold, Tobias; Belka, Claus; Misra, Ritu; Bassermann, Florian; Garcia-Saez, Ana J. und Jost, Philipp J. (2021): MLKL promotes cellular differentiation in myeloid leukemia by facilitating the release of G-CSF. In: Cell Death and Differentiation, Bd. 28, Nr. 12: S. 3235-3250

Abstract

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1350-9047
• Sprache: Englisch