|ZFIN ID: ZDB-PUB-150318-6|
Functions of idh1 and its mutation in the regulation of developmental hematopoiesis in zebrafish
Shi, X., He, B.L., Ma, A.C., Guo, Y., Chi, Y., Man, C.H., Zhang, W., Zhang, Y., Wen, Z., Cheng, T., Leung, A.Y.
|Source:||Blood 125(19): 2974-84 (Journal)|
|Registered Authors:||Chi, Yali, Leung, Anskar, Wen, Zilong|
|PubMed:||25778530 Full text @ Blood|
Shi, X., He, B.L., Ma, A.C., Guo, Y., Chi, Y., Man, C.H., Zhang, W., Zhang, Y., Wen, Z., Cheng, T., Leung, A.Y. (2015) Functions of idh1 and its mutation in the regulation of developmental hematopoiesis in zebrafish. Blood. 125(19):2974-84.
ABSTRACTIsocitrate dehydrogenase 1 mutation (IDH1-R132H) was recently identified in acute myeloid leukemia (AML) with normal cytogenetics. The mutant enzyme is thought to convert α-ketoglutarate (α-KG) to the pathogenic 2-hydroxyglutarate (2-HG) that affects DNA methylation via inhibition of ten-eleven translocation 2 (TET2). However, the role of wild type IDH1 in normal hematopoiesis and its relevance to AML is unknown. Here we showed that zebrafish idh1 (zidh1) knockdown by morpholino and targeted mutagenesis by transcription activator-like effector nuclease (TALEN) 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 mRNA, suggesting non-redundant functions. Over-expression of human IDH1-R132H or its zebrafish orthologue 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 responses in human but not zebrafish IDH1 mutant expression. The results provided important insights to the role of zidh1 in myelopoiesis and definitive hematopoiesis and of IDH1-R132H in leukemogenesis.