Potential role of short-chain fatty acids in the pathogenesis and management of acute lymphocytic leukemia.

ABSTRACT

Acute lymphocytic leukemia (ALL) is an aggressive hematological malignancy of highly proliferative lymphoblasts. ALL is the most common cancer in children, and is typically treated with combination chemotherapy. The 5-year survival of ALL improved significantly in recent decades with this treatment approach. However, certain age groups (below 2 and over 10 years of age) have much worse prognosis, and over 50% of patients with ALL experience long-term side effects proportional to the dosage of anticancer drugs. Therefore, different treatment strategies are required to improve survival in ALL and to reduce side effects of chemotherapy. Since epigenetic modifications are dominantly reversible, "epidrugs" (drugs targeting epigenetic markers) are considered for feasibility in the treatment of ALL as epigenetic modifications, and acetylation of histones was demonstrated to play a critical role in the pathogenesis of ALL. Histone deacetylases (HDACs) have been shown to be differentially expressed in several hematological malignancies, including ALL. HDAC inhibitors (HDACis) have been shown to express selective toxicity for ALL cells, but they showed limited efficacy and higher than expected toxicity in mouse models or clinical trials in ALL. The aim of this review is to examine the role of the microbiota and microbial metabolites in the mechanisms of HDAC functions, and explore the utilization of the microbiota and microbial metabolites in improving the efficacy of HDACi in ALL. HDAC regulators and natural HDACi are depleted in ALL due to microbiota change leading to a decrease in butyrate and propionate, and HDACi treatment is not effective in ALL due to their short half-life. We propose that HDACi released by the microbiota may be necessary in HDAC regulation and this process is impaired in ALL. Furthermore, the review will also consider the role of restoration of the microbiota or supplementation of natural HDACi in potentially restoring HDAC and HDACi functions.