Cargando…

Fumarate hydratase deficiency induces chronic myeloid leukemia progression

BACKGROUND: Although tyrosine kinase inhibitors (TKIs) have profoundly improved the prognosis of chronic myeloid leukemia (CML), the mechanism of the progression to blast phase (BP) is currently unclear. Our previous study indicated that CML-BP cells utilize glycolysis to proliferate and that the fu...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Shan, Qiao, Chun, Yang, Lijia, Hong, Ming, Fang, Yu, Jin, Hui, Li, Jianyong, Qian, Sixuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: AME Publishing Company 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8797861/
https://www.ncbi.nlm.nih.gov/pubmed/35116792
http://dx.doi.org/10.21037/tcr.2019.03.23
_version_ 1784641655585898496
author Li, Shan
Qiao, Chun
Yang, Lijia
Hong, Ming
Fang, Yu
Jin, Hui
Li, Jianyong
Qian, Sixuan
author_facet Li, Shan
Qiao, Chun
Yang, Lijia
Hong, Ming
Fang, Yu
Jin, Hui
Li, Jianyong
Qian, Sixuan
author_sort Li, Shan
collection PubMed
description BACKGROUND: Although tyrosine kinase inhibitors (TKIs) have profoundly improved the prognosis of chronic myeloid leukemia (CML), the mechanism of the progression to blast phase (BP) is currently unclear. Our previous study indicated that CML-BP cells utilize glycolysis to proliferate and that the fumarate level is elevated in CML-BP cells. Fumarate hydratase (FH) catalyzes fumarate to malate. A functional deficiency in FH could result in fumarate accumulation. Therefore, we wanted to determine whether an FH deficiency facilitates CML progression. METHODS: FH expression in CML chronic phase (CP) and CML-BP was analyzed. In vitro, we tested whether FH expression knockdown induces glycolysis and increases K562 cell invasiveness. DNA damage repair after FH expression knockdown was also tested. RESULTS: Our findings showed that CML-BP patients had lower FH expression than CML-CP patients (P=0.025). Knocking down FH expression enhanced the invasiveness of K562 cells through HIF-1α-induced glycolysis. DNA damage repair was impaired after FH expression knockdown. CONCLUSIONS: Our findings suggested that reduced FH function may facilitate disease progression in CML through the combined effects of an elevated glycolysis level and a decreased DNA repair ability.
format Online
Article
Text
id pubmed-8797861
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher AME Publishing Company
record_format MEDLINE/PubMed
spelling pubmed-87978612022-02-02 Fumarate hydratase deficiency induces chronic myeloid leukemia progression Li, Shan Qiao, Chun Yang, Lijia Hong, Ming Fang, Yu Jin, Hui Li, Jianyong Qian, Sixuan Transl Cancer Res Original Article BACKGROUND: Although tyrosine kinase inhibitors (TKIs) have profoundly improved the prognosis of chronic myeloid leukemia (CML), the mechanism of the progression to blast phase (BP) is currently unclear. Our previous study indicated that CML-BP cells utilize glycolysis to proliferate and that the fumarate level is elevated in CML-BP cells. Fumarate hydratase (FH) catalyzes fumarate to malate. A functional deficiency in FH could result in fumarate accumulation. Therefore, we wanted to determine whether an FH deficiency facilitates CML progression. METHODS: FH expression in CML chronic phase (CP) and CML-BP was analyzed. In vitro, we tested whether FH expression knockdown induces glycolysis and increases K562 cell invasiveness. DNA damage repair after FH expression knockdown was also tested. RESULTS: Our findings showed that CML-BP patients had lower FH expression than CML-CP patients (P=0.025). Knocking down FH expression enhanced the invasiveness of K562 cells through HIF-1α-induced glycolysis. DNA damage repair was impaired after FH expression knockdown. CONCLUSIONS: Our findings suggested that reduced FH function may facilitate disease progression in CML through the combined effects of an elevated glycolysis level and a decreased DNA repair ability. AME Publishing Company 2019-04 /pmc/articles/PMC8797861/ /pubmed/35116792 http://dx.doi.org/10.21037/tcr.2019.03.23 Text en 2019 Translational Cancer Research. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
spellingShingle Original Article
Li, Shan
Qiao, Chun
Yang, Lijia
Hong, Ming
Fang, Yu
Jin, Hui
Li, Jianyong
Qian, Sixuan
Fumarate hydratase deficiency induces chronic myeloid leukemia progression
title Fumarate hydratase deficiency induces chronic myeloid leukemia progression
title_full Fumarate hydratase deficiency induces chronic myeloid leukemia progression
title_fullStr Fumarate hydratase deficiency induces chronic myeloid leukemia progression
title_full_unstemmed Fumarate hydratase deficiency induces chronic myeloid leukemia progression
title_short Fumarate hydratase deficiency induces chronic myeloid leukemia progression
title_sort fumarate hydratase deficiency induces chronic myeloid leukemia progression
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8797861/
https://www.ncbi.nlm.nih.gov/pubmed/35116792
http://dx.doi.org/10.21037/tcr.2019.03.23
work_keys_str_mv AT lishan fumaratehydratasedeficiencyinduceschronicmyeloidleukemiaprogression
AT qiaochun fumaratehydratasedeficiencyinduceschronicmyeloidleukemiaprogression
AT yanglijia fumaratehydratasedeficiencyinduceschronicmyeloidleukemiaprogression
AT hongming fumaratehydratasedeficiencyinduceschronicmyeloidleukemiaprogression
AT fangyu fumaratehydratasedeficiencyinduceschronicmyeloidleukemiaprogression
AT jinhui fumaratehydratasedeficiencyinduceschronicmyeloidleukemiaprogression
AT lijianyong fumaratehydratasedeficiencyinduceschronicmyeloidleukemiaprogression
AT qiansixuan fumaratehydratasedeficiencyinduceschronicmyeloidleukemiaprogression