Universität zu Köln

Wang, Xin, Ros, Uris, Agrawal, Deepti ORCID: 0000-0002-9541-1704, Keller, Eva C., Slotta-Huspenina, Julia, Dill, Veronika, Shen, Bo, Shi, Run ORCID: 0000-0003-4667-4812, Herold, Tobias, Belka, Claus, Misra, Ritu, Bassermann, Florian, Garcia-Saez, Ana J. and Jost, Philipp J. ORCID: 0000-0003-2454-0362 (2021). MLKL promotes cellular differentiation in myeloid leukemia by facilitating the release of G-CSF. Cell Death Differ., 28 (12). S. 3235 - 3251. LONDON: SPRINGERNATURE. ISSN 1476-5403

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Wang, Xin UNSPECIFIED UNSPECIFIED UNSPECIFIED Ros, Uris UNSPECIFIED UNSPECIFIED UNSPECIFIED Agrawal, Deepti UNSPECIFIED orcid.org/0000-0002-9541-1704 UNSPECIFIED Keller, Eva C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Slotta-Huspenina, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Dill, Veronika UNSPECIFIED UNSPECIFIED UNSPECIFIED Shen, Bo UNSPECIFIED UNSPECIFIED UNSPECIFIED Shi, Run UNSPECIFIED orcid.org/0000-0003-4667-4812 UNSPECIFIED Herold, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Belka, Claus UNSPECIFIED UNSPECIFIED UNSPECIFIED Misra, Ritu UNSPECIFIED UNSPECIFIED UNSPECIFIED Bassermann, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Garcia-Saez, Ana J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jost, Philipp J. UNSPECIFIED orcid.org/0000-0003-2454-0362 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-597260
DOI:	10.1038/s41418-021-00811-1
Journal or Publication Title:	Cell Death Differ.
Volume:	28
Number:	12
Page Range:	S. 3235 - 3251
Date:	2021
Publisher:	SPRINGERNATURE
Place of Publication:	LONDON
ISSN:	1476-5403
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MIXED LINEAGE KINASE; COLONY-STIMULATING FACTOR; DOMAIN-LIKE PROTEIN; MEDIATES NECROPTOSIS; RETINOIC ACID; EXPRESSION; DEATH; GRANULOCYTE; DOWNSTREAM; CANCER Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59726