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SMARCA5 reprograms AKR1B1-mediated fructose metabolism to control leukemogenesis.
- Source :
-
Developmental cell [Dev Cell] 2024 Aug 05; Vol. 59 (15), pp. 1954-1971.e7. Date of Electronic Publication: 2024 May 21. - Publication Year :
- 2024
-
Abstract
- A significant variation in chromatin accessibility is an epigenetic feature of leukemia. The cause of this variation in leukemia, however, remains elusive. Here, we identify SMARCA5, a core ATPase of the imitation switch (ISWI) chromatin remodeling complex, as being responsible for aberrant chromatin accessibility in leukemia cells. We find that SMARCA5 is required to maintain aberrant chromatin accessibility for leukemogenesis and then promotes transcriptional activation of AKR1B1, an aldo/keto reductase, by recruiting transcription co-activator DDX5 and transcription factor SP1. Higher levels of AKR1B1 are associated with a poor prognosis in leukemia patients and promote leukemogenesis by reprogramming fructose metabolism. Moreover, pharmacological inhibition of AKR1B1 has been shown to have significant therapeutic effects in leukemia mice and leukemia patient cells. Thus, our findings link the aberrant chromatin state mediated by SMARCA5 to AKR1B1-mediated endogenous fructose metabolism reprogramming and shed light on the essential role of AKR1B1 in leukemogenesis, which may provide therapeutic strategies for leukemia.<br />Competing Interests: Declaration of interests The authors declare no competing interests.<br /> (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Humans
Mice
Adenosine Triphosphatases
Aldehyde Reductase metabolism
Aldehyde Reductase genetics
Carcinogenesis metabolism
Carcinogenesis pathology
Carcinogenesis genetics
Cell Line, Tumor
Chromatin metabolism
Chromatin Assembly and Disassembly
Chromosomal Proteins, Non-Histone metabolism
Chromosomal Proteins, Non-Histone genetics
Leukemia metabolism
Leukemia pathology
Leukemia genetics
Transcription Factors metabolism
Transcription Factors genetics
Fructose metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1878-1551
- Volume :
- 59
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Developmental cell
- Publication Type :
- Academic Journal
- Accession number :
- 38776924
- Full Text :
- https://doi.org/10.1016/j.devcel.2024.04.023