Anti-Tumor Effects of BDH1 in Acute Myeloid Leukemia.

Fei Han,Yude Lou,Jun Lu,Xi Jiang,Jie Sun,Dan Su,Qishan Wang,Lingling Yang,Xiang Li,Shixuan Zhang,He Huang,Xin Chen,Huanhuan Zhao,Hanwei Jin,Weina Yun

doi:10.3389/fonc.2021.694594

Abstract

Dysregulation of ketone metabolism has been reported in various types of cancer. In order to find out its role in acute myeloid leukemia (AML) pathogenesis, we first analyzed the expression levels of 10 key genes involved in ketone metabolism in AML blasts and CD34+ hematopoietic stem cells (HSCs) from healthy donors. We found that the expression level of BDH1 was significantly lower in AML than in normal HSCs. The downregulation of BDH1 gene expression in AML cell lines as compared with normal HSCs was further confirmed with real-time RT-PCR. Analysis of TCGA and other database revealed that the downregulation of BDH1 was associated with worse prognosis in AML patients. In addition, we showed that overexpression of BDH1 inhibited the viability and proliferation of AML cells. In contrast, BDH1 knock-down promoted AML cell growth. Collectively, our results suggest the previously unappreciated anti-tumor role of BDH1 in AML, and low BDH1 expression predicts poor survival.

Highlights

Acute myeloid leukemia (AML), the most common type of acute leukemia in adults, is a group of highly aggressive heterogeneous cancer [1]
We show the downregulation of key genes involved in ketone body metabolism in acute myeloid leukemia (AML) blasts as compared with normal hematopoietic stem cells (HSCs), and identify the association between BDH1 expression and AML prognosis
To explore the expression pattern of genes participating in ketogenesis and ketolysis in AML, a total of 10 genes from “Synthesis and degradation of ketone bodies” of Kyoto Encyclopedia of Genes and Genomes (KEGG) were selected for the following analysis (Table 1)

Summary

Introduction

Acute myeloid leukemia (AML), the most common type of acute leukemia in adults, is a group of highly aggressive heterogeneous cancer [1]. Despite of intensive traditional chemotherapy, the overall 3-year survival of AML patients was only around 25%. Many subtypes of AML are associated with intermediate to poor prognosis, especially in elder patients [2]. It is urgently needed to better understand the molecular mechanism of AML, and develop novel therapy targeting key molecules crucial for leukemogenesis. Dysregulation of metabolism, including the aerobic glycolysis [3,4,5], the amino acid [6] and fatty acid metabolism [7, 8], has been found in cancer, including AML. Targeting metabolic pathways provides a potential strategy for cancer therapy [9]. A bunch of regulators, such as the 3-hydroxymethylglutaryl-CoA synthase (HMGCS2), the hydroxymethylglutaryl coenzyme A lyase (HMGCL), the 3-oxoacid CoA transferase 1 (OXCT1), and the phosphatidylcholine-dependent mitochondrial bOHB dehydrogenase (BDH1), etc., are

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Discussion

Conclusion