Journal Article

Pivotal role of DPYSL2A in KLF4-mediated monocytic differentiation of acute myeloid leukemia cells

Morita, Ken, Adachi, Souichi, Kamikubo, Yasuhiko, Noura, Mina, Matsuo, Hidemasa, Nishinaka-Arai, Yoko, Kiyose, Hiroki, Kurokawa, Mineo

2020

Overview

Although the biological importance of Krüppel-like factor 4 (KLF4) transcription factor in the terminal differentiation of hematopoietic cells to the monocytes has been well established, the underlying mechanisms remain elusive. To clarify the molecular basis of KLF4-mediated monocytic differentiation, we performed detailed genetic studies in acute myeloid leukemia (AML) cells. Here, we report that dihydropyrimidinase like 2 (DPYSL2), also known as CRMP2, is a novel key differentiation mediator downstream of KLF4 in AML cells. Interestingly, we discovered that KLF4-mediated monocytic differentiation is selectively dependent on one specific isoform, DPYSL2A, but not on other DPYSL family genes. Terminal differentiation to the monocytes and proliferation arrest in AML cells induced by genetic or pharmacological upregulation of KLF4 were significantly reversed by short hairpin RNA (shRNA)-mediated selective depletion of DPYSL2A. Chromatin immunoprecipitation assay revealed that KLF4 associates with the proximal gene promoter of DPYSL2A and directly transactivates its expression. Together with the unique expression patterns of KLF4 and DPYSL2 limited to the differentiated monocytes in the hematopoietic system both in human and mouse, the identified KLF4-DPYSL2 axis in leukemia cells may serve as a potential therapeutic target for the development of novel differentiation therapies for patients with AML.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/1990/283 / 631/67/1990/283/1897 / Acute myeloid leukemia / Cell differentiation / Cell Differentiation - physiology / Cell Line, Tumor / Cell proliferation / Chromatin / Dihydropyrimidinase / Gene Expression Regulation, Leukemic / Humanities and Social Sciences / Humans / Immunoprecipitation / Intercellular Signaling Peptides and Proteins - physiology / KLF4 protein / Kruppel-Like Transcription Factors - physiology / Leukemia / Leukemia, Myeloid, Acute - genetics / Leukemia, Myeloid, Acute - pathology / Monocytes / Monocytes - cytology / multidisciplinary / Myeloid leukemia / Nerve Tissue Proteins - physiology / Promoter Regions, Genetic / Ribonucleic acid / RNA / Science / Science (multidisciplinary)