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Wang, X.* ; Ros, U.* ; Agarwal, D.* ; Keller, E.C.* ; Slotta-Huspenina, J.* ; Dill, V.* ; Shen, B.* ; Shi, R.* ; Herold, T. ; Belka, C.* ; Misra, R.* ; Bassermann, F.* ; García-Sáez, A.J.* ; Jost, P.J.*

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

Cell Death Differ. 28, 3235–3250 (2021)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Mixed Lineage Kinase; Colony-stimulating Factor; Domain-like Protein; Mediates Necroptosis; Retinoic Acid; Expression; Death; Granulocyte; Downstream; Cancer
ISSN (print) / ISBN 1350-9047
e-ISSN 1476-5403
Zeitschrift Cell Death and Differentiation
Quellenangaben Band: 28, Heft: , Seiten: 3235–3250 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort Campus, 4 Crinan St, London, N1 9xw, England
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)
Förderungen Else Kroner Fresenius Stiftung
Deutsche Jose Carreras Leukamie-Stiftung
Deutsche Forschungsgemeinschaft
Deutsche Konsortium fur Translationale Krebsforschung (DKTK) of the German Cancer Center (DKFZ)
China Scholarship Council
European Research Council (project BCM-UPS)
WilhelmSander-Stiftung
Physician Scientists Grant from the Helmholtz Zentrum Munchen
Projekt DEAL
Max Eder-Program grant from the Deutsche Krebshilfe