Involvement of the translation machinery in the improvement of anemia in myelodysplastic syndromes by Aza-dC

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08357
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Hiroshima University
• Principal Investigator: Nagamachi Akiko 広島大学, 原爆放射線医科学研究所, 助教 (20585153)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 骨髄異形成症候群 / アザシチジン

Outline of Final Research Achievements

Accumulating evidence has demonstrated successful epigenetic therapy by targeting DNA demethylation with Aza/Aza-dC in MDS. However, the mechanism by which Aza/Aza-dC induces Hb synthesis is still largely unknown. To identify the direct targets of Aza-dC, we applied whole genome methylation and transcriptome analysis to K562 cells, in which Hb synthesis was significantly enhanced. This identified that a translational regulator, eEF1A2 was greatly induced by Aza-dC, coupled with significant DNA demethylation of the gene promoter. BMT assay using eEF1A2-deficient mice and ATAC-seq analysis, which identifies genome wide open chromatin regions revealed that the related eEF1A1 gene mainly contributes to hematopoiesis. These data indicated that the ectopic expression of eEF1A2 is a mechanism through which Aza-dC improves the anemia of MDS patients.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

本研究は複雑なエピゲノム変動を伴うMDS細胞を用いた臨床側からのアプローチではなく、K562細胞株というシンプルな実験系で赤血球分化に標的を絞ったアプローチであり、得られた翻訳効率の関与という新しい知見と本研究での解析結果は、Azaの作用機序への理解をさらに進めるものであると考えられる。