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.
Highlights
Acute myeloid leukemia (AML) is a cancer of the myeloid compartment characterized by a block of leukemic cells at different levels along the myeloid differentiation process
In order to establish a role for ALFY in the granulocytic differentiation of AML cells, we exposed NB4 and HT93 acute promyelocytic leukemia (APL) as well as HL60 AML cells to all-trans retinoic acid (ATRA) for different amounts of time
To support the idea that ATRA–triggered induction of ALFY mRNA is dependent on granulocytic differentiation, similar experiments were performed in the ATRAresistant sub-clones NB4-R2 and HL60-R2
Summary
Acute myeloid leukemia (AML) is a cancer of the myeloid compartment characterized by a block of leukemic cells at different levels along the myeloid differentiation process. Pharmacological doses of ATRA overcome the PML-RARα mediated differentiation block of APL cells. ATRA leads to high rates of complete remission due to the induction of granulocytic differentiation and subsequent cell death, the available clinical data indicate that ATRA monotherapy invariably leads to relapse of the disease This has led to the idea that targeting of leukemia initiating cells (LICs) by ATRA is inefficient[9]. Upon autophagy-induction, ALFY translocates from the nucleus to the cytoplasm where it assists p62 in the autophagy-dependent degradation of ubiqutinated protein aggregates in neurodegenerative diseases[22,23]. All this prompted us to investigate the role of ALFY in myeloid differentiation and aggrephagy
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