Human BDH2 As a Predictor for Leukemia Progression in Myelodysplastic Syndrome

Objective: Myelodysplastic syndrome (MDS) is a disorder of hematopoietic stem cells. In MDS patients, leukemia progression is associated with iron overload. Hydroxybutyrate dehydrogenase type 2 (BDH2) catalyzes the production of 2,5-dihydroxybenzoic acid (DHBA), an iron-binding component.

Methods: The bone marrow (BM) of 187 MDS patients, 119 de novo acute myeloid leukemia (AML) patients, and 43 lymphoma patients (stage I-III) with normal BM were analyzed. BDH2mRNA expressions from BM and BDH2-KD THP1 were analyzed using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Cell cycle and cell maturation were determined by flowcytometry and surface markers in RNA interference–mediated-knockdown of BDH2 (BDH2-KD) THP1, an acute leukemia cell line. Immunohistochemistry was performed to detect BDH2 protein expression in the bone marrow.

Results: Elevated BDH2mRNA expression was observed in bone marrow in MDS patients (P=0.009) and was related to ferritin levels (P=0.049). The higher BDH2 expression (15%) group showed a greater risk for leukemia progression than the lower expression group (3.18%) (P=0.017). Leukemia-free-survival was longer in patients with low BDH2mRNA expression (P=0.028) and patients with ferritin level <1000 ng/mL. Additionally, cell cycle analysis, surface markers, and special stain studies indicated that BDH2-KD induced differentiation and decreased the growth rate of THP1 cells, which was associated with the retardation of cell cycle.

Conclusions: We identified new molecular mechanisms of BDH2. BDH2 is involved in cell cycle arrest and inhibition of differentiation in malignant cells. Further, high BDH2 expression in MDS patients suggest that it could act as a poor prognostic factor.