Schläfli, Anna; Isakson, Pauline; Garattini, E; Simonsen, Anne; Tschan, Mario (2017). The autophagy scaffold protein ALFY is critical for the granulocytic differentiation of AML cells. Scientific Reports, 7(1), p. 12980. Nature Publishing Group 10.1038/s41598-017-12734-4
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Acute myeloid leukemia (AML) is a malignancy of myeloid progenitor cells that are blocked in differentiation. Acute promyelocytic leukemia (APL) is a rare form of AML, which generally presents with a t(15;17) translocation causing expression of the fusion protein PML-RARA. Pharmacological doses of all-trans retinoic acid (ATRA) induce granulocytic differentiation of APL cells leading to cure rates of >80% if combined with conventional chemotherapy. Autophagy is a lysosomal degradation pathway for the removal of cytoplasmic content and recycling of macromolecules. ATRA induces autophagy in ATRA-sensitive AML and APL cells and autophagy inhibition attenuates ATRA-triggered differentiation. In this study, we aimed at identifying if the autophagy-linked FYVE-domain containing protein (ALFY/WDFY3) is involved in autophagic degradation of protein aggregates contributes to ATRA therapy-induced autophagy. We found that ALFY mRNA levels increase significantly during the course of ATRA-induced differentiation of APL and AML cell lines. Importantly ALFY depletion impairs ATRA-triggered granulocytic differentiation of these cells. In agreement with its function in aggrephagy, knockdown of ALFY results in reduced ATRA-induced proteolysis. Our data further suggest that PML-RARα is an autophagy substrate degraded with the help of ALFY. In summary, we present a crucial role for ALFY in retinoid triggered maturation of AML cells.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology 04 Faculty of Medicine > Service Sector > Institute of Pathology |
Graduate School: |
Graduate School for Cellular and Biomedical Sciences (GCB) |
UniBE Contributor: |
Bill, Anna Magdalena, Tschan, Mario Paul |
Subjects: |
500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health |
ISSN: |
2045-2322 |
Publisher: |
Nature Publishing Group |
Language: |
English |
Submitter: |
Mario Tschan |
Date Deposited: |
16 Nov 2017 08:31 |
Last Modified: |
05 Dec 2022 15:07 |
Publisher DOI: |
10.1038/s41598-017-12734-4 |
PubMed ID: |
29021535 |
BORIS DOI: |
10.7892/boris.106362 |
URI: |
https://boris.unibe.ch/id/eprint/106362 |
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