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Researchers Link Aberrant Chromatin Accessibility to Endogenous Fructose Metabolism Reprogramming in Leukemogenesis

May 22, 2024

A research team led by Dr. WANG Lan from the Shanghai Institute of Nutrition and Health (SINH) of the Chinese Academy of Sciences (CAS), identified a linkage between aberrant epigenetic chromatin accessibility and reprogrammed endogenous fructose metabolism in the regulation of leukemogenesis. This study was published online in Developmental Cell on May 21. 

Acute myeloid leukemia (AML) is a kind of hematological malignancy derived from the abnormal clonal proliferation of hematopoietic stem cells (HSCs), characterized by impaired hematopoiesis and myelodysplasia, and has a poor prognosis. Chemotherapy is still the major treatment of AML patients, while there is a high frequency of relapse after treatment. It is needed to dissect the underlying mechanism of leukemogenesis to develop novel strategies of AML. Recent studies have identified a significant variation in chromatin accessibility as a novel feature of AML, while the factors responsible for this alteration is still elusive.

Metabolic reprogramming is closely related to tumorigenesis, including leukemogenesis. Exogenous fructose has been shown to be essential to promote the development of AML, and since it is known that endogenous fructose can also be generated from glucose via the polyol pathway, the question of whether this endogenous fructose is also essential for leukemogenesis remains elusive. 

To systematically identify the factors responsible for the aberrant of chromatin accessibility in AML, researchers performed CRISPR screening in AML cells. They found that SMARCA5, an ATPase of the ISWI chromatin remodeling complex, is primarily responsible for the aberrant chromatin accessibility in AML.

Through the combined analysis using multiple databases, AML cell lines, conditional knockout mice and samples of AML patients, researchers showed that SMARCA5 is indeed essential for leukemogenesis in vitro and in vivo. 

Mechanistically, using RNA-seq, ATAC-seq, CUT&Tag and metabonomics, researchers found that SMARCA5 mediated open chromatin accessibility could promote the expression of AKR1B1, an aldo/keto reductase, by recruiting transcription co-activator DDX5 and transcription factor SP1, and then higher expression of AKR1B1 could reprogram endogenous fructose metabolism to contribute to leukemogenesis.

The treatment of AML with epalrestat, a clinical inhibitor of AKR1B1, was shown to be effective, which may offer a new therapeutic strategy for leukemia.

Contact

WANG Jin

Shanghai Institute of Nutrition and Health

E-mail:

SMARCA5 reprograms AKR1B1-mediated fructose metabolism to control leukemogenesis

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