Functions of idh1 and its mutation in the regulation of developmental hematopoiesis in zebrafish.

Blood
Xiangguo ShiA Y H Leung

Abstract

Isocitrate dehydrogenase 1 mutation (IDH1-R132H) was recently identified in acute myeloid leukemia with normal cytogenetics. The mutant enzyme is thought to convert α-ketoglutarate to the pathogenic 2-hydroxyglutarate (2-HG) that affects DNA methylation via inhibition of ten-eleven translocation 2. However, the role of wild-type IDH1 in normal hematopoiesis and its relevance to acute myeloid leukemia is unknown. Here we showed that zebrafish idh1 (zidh1) knockdown by morpholino and targeted mutagenesis by transcription activator-like effector nuclease might induce blockade in myeloid differentiation, as evident by an increase in pu.1 and decrease in mpo, l-plastin, and mpeg1 expression, and significantly reduce definitive hematopoiesis. Morpholino knockdown of zidh2 also induced a blockade in myeloid differentiation but definitive hematopoiesis was not affected. The hematopoietic phenotype of zidh1 knockdown was not rescuable by zidh2 messenger RNA, suggesting nonredundant functions. Overexpression of human IDH1-R132H or its zebrafish ortholog resulted in 2-HG elevation and expansion of myelopoiesis in zebrafish embryos. A human IDH1-R132H-specific inhibitor (AGI-5198) significantly ameliorated both hematopoietic and 2-HG respo...Continue Reading

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Citations

Jan 30, 2016·Journal of Biomedical Science·Cheng-Yung LinHuai-Jen Tsai
Oct 8, 2015·Blood Reviews·Xiangguo ShiAnskar Y H Leung
Feb 13, 2018·Wiley Interdisciplinary Reviews. Developmental Biology·Aniket V GoreBrant M Weinstein
Dec 20, 2017·Frontiers in Oncology·Kathryn S Potts, Teresa V Bowman
Sep 15, 2019·Disease Models & Mechanisms·Martina KonantzClaudia Lengerke

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