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The autophagy scaffold protein ALFY is critical for the granulocytic differentiation of AML cells.

The autophagy scaffold protein ALFY is critical for the granulocytic differentiation of AML cells.
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Schläfli AM, Isakson P, Garattini E, Simonsen A, Tschan MP,


Schläfli AM, Isakson P, Garattini E, Simonsen A, Tschan MP, (click to view)

Schläfli AM, Isakson P, Garattini E, Simonsen A, Tschan MP,

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Scientific reports 2017 10 117(1) 12980 doi 10.1038/s41598-017-12734-4
Abstract

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.

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