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Open Access Green as soon as Postprint is submitted to ZB.
Leukemia cells accumulate zinc for oncofusion protein stabilization.
J. Nutr. Biochem. 123:11 (2024)
Acute promyelocytic leukemia (APL) and chronic myeloid leukemia (CML) are both hematological malignancies characterized by genetic alterations leading to the formation of oncofusion proteins. The classical chromosomal aberrations in APL and CML result in the PML-RARα and BCR-ABL1 oncofusion proteins, respectively. Interestingly, our flow cytometric analyses revealed elevated free intracellular zinc levels in various leukemia cells, which may play a role in stabilizing oncofusion proteins in leukemia and thus support cell proliferation and malignancy. Long-term zinc deficiency resulted in the degradation of PML-RARα in NB4 cells (APL cell line) and of BCR-ABL1 in K562 cells (CML cell line). This degradation may be explained by increased caspase 3 activity observed in zinc deficient cells, whereas zinc reconstitution normalized the caspase 3 activity and abolished zinc deficiency-induced oncofusion protein degradation. In NB4 cells, fluorescence microscopic images further indicated enlarged and enriched lysosomes during zinc deficiency, suggesting increased rates of autophagy. Moreover, NB4 cells exhibited increased expression of the zinc transporters ZIP2, ZIP10 and ZnT3 during zinc deficiency and revealed excessive accumulation of zinc in contrast to healthy peripheral blood mononuclear cells (PBMCs), when zinc was abundantly available extracellularly. Our results highlight the importance of altered zinc homeostasis for some characteristics in leukemia cells, uncover potential pathways underlying the effects of zinc deficiency in leukemia cells, and provide potential alternative strategies by which oncofusion proteins can be degraded.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Caspase 3 ; Leukemia ; Oncofusion Protein ; Zinc Homeostasis ; Zinc Transporters; Rar-alpha; Intracellular Zinc; Induced Differentiation; Positive Leukemia; Fusion Gene; K562 Cells; Degradation; Homeostasis; Expression; Apoptosis
ISSN (print) / ISBN
0955-2863
e-ISSN
0955-2863
Quellenangaben
Volume: 123,
Article Number: 11
Publisher
Elsevier
Publishing Place
Ste 800, 230 Park Ave, New York, Ny 10169 Usa
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute for Allergy Research (IAF)